CN103121995B - 3-alkyl-5-(4-alkyl-5-oXo-tetrahydro furan-2-base) pyrrolidin-2-one derivatives as the intermediate of synthesis renin inhibitor - Google Patents
3-alkyl-5-(4-alkyl-5-oXo-tetrahydro furan-2-base) pyrrolidin-2-one derivatives as the intermediate of synthesis renin inhibitor Download PDFInfo
- Publication number
- CN103121995B CN103121995B CN201210566662.6A CN201210566662A CN103121995B CN 103121995 B CN103121995 B CN 103121995B CN 201210566662 A CN201210566662 A CN 201210566662A CN 103121995 B CN103121995 B CN 103121995B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- alkyl
- salt
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 *[C@](C[C@@]([C@@](C[C@]1*)OC1=O)N1)C1=O Chemical compound *[C@](C[C@@]([C@@](C[C@]1*)OC1=O)N1)C1=O 0.000 description 7
- HKQZJXVIXAPOPZ-UHFFFAOYSA-N CC(C)(CN)C(N)=O Chemical compound CC(C)(CN)C(N)=O HKQZJXVIXAPOPZ-UHFFFAOYSA-N 0.000 description 1
- IMCGHZIGRANKHV-WUCCLRPBSA-N CC(C)C(C[C@@H]([C@H](CC1C(C)C)OC1=O)N1C(OC(C)(C)C)=O)C1=O Chemical compound CC(C)C(C[C@@H]([C@H](CC1C(C)C)OC1=O)N1C(OC(C)(C)C)=O)C1=O IMCGHZIGRANKHV-WUCCLRPBSA-N 0.000 description 1
- FKJVUNWGCHATNU-BJDJZHNGSA-N CC(C)[C@H](C[C@@H]([C@H](C[C@H]1C(C)=C)OC1=O)N1)C1=O Chemical compound CC(C)[C@H](C[C@@H]([C@H](C[C@H]1C(C)=C)OC1=O)N1)C1=O FKJVUNWGCHATNU-BJDJZHNGSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to 3 alkyl 5 (4 alkyl 5 oxo-tetrahydrofuran 2 base) pyrrolidine 2 ketone derivatives as the intermediate synthesizing renin inhibitor.In particular it relates to a kind of compound for synthesizing pharmaceutical active, especially renin inhibitor, such as the new method of aliskiren, new procedure of processing and some new intermediates.In particular, the present invention relates to a kind of method of the compound or its salt preparing Formula II, the compound or its salt of Formula IV and the method manufacturing these compounds, wherein R3And R4And the definition of Act is as noted in the discussion.Further being converted compound (VI) with metallo-organic compound (VII), obtain noval chemical compound (VIII), it is the direct precursor preparing aliskiren.
Description
The application be on October 16th, 2006 submit to Application No. PCT/EP2006/009970, invention entitled " as
3-alkyl-5-(4-alkyl-5-oXo-tetrahydro furan-2-base) pyrrolidin-2-one of the intermediate of synthesis renin inhibitor derives
Thing " the divisional application of international application, this international application enters National Phase in China, Application No. on July 31st, 2007
200680003597.9。
Technical field
The present invention relates to novel C-8 lactams lactone compound.Additionally, present invention also offers for preparing these C-
The method of 8 lactams lactone compounds.
These C-8 lactams lactone compounds be more specifically formula (II) as shown below 5-(5-oXo-tetrahydro-
Furan-2-base) pyrrolidin-2-one compounds.This compounds is renin inhibitor, particularly 2 (S), 4 (S), 5 (S), 7 (S)-
Key in the preparation of 2,7-dialkyl group-4-hydroxyl-5-amino-8-aryl-caprylyl amide derivatives or its pharmaceutically useful salt
Intermediate.Therefore, the invention still further relates to intermediate useful in the preparation of these renin inhibitors and for preparing these
Renin inhibitor and the method for intermediate thereof.
Background technology
Feritin is flowed into blood flow from kidney, and it makes proangiotensin crack in blood flow, the vasotonia of release decapeptide
Element I, the latter is cleaved in lung, kidney and other organ subsequently, thus forms the Angiotensin II of octapeptide.This octapeptide is by dynamic
Arteries and veins vasoconstriction and directly increase blood pressure or retain the hormone aldosterone of sodium ion by being discharged by adrenal gland and indirectly increase
Having added blood pressure, the latter is attributable to the effect of Angiotensin II with the increase of extracellular fluid volume, described volume increase.
The inhibitor of feritin enzymatic activity reduces the formation of angiotensin I, and therefore reduces produced Angiotensin II
Quantity.The reduction of this active peptide hormone concentration is the immediate cause of renin inhibitor hypotensive activity.
With compound such as (INN title) aliskiren ((2S, 4S, 5S, S)-5-amino-N-(2-carbamoyl-2-first
Base propyl group)-4-hydroxyl-2-isopropyl-7-[4-methoxyl group-3-(3-methoxy propoxy) benzyl]-8-methyl pelargonamide
(nonanamide)) together, have developed a kind of new antihypertensive, it is when Angiotensin II biosynthesis starts
Disturb renin-angiotensin system.
Because this compound comprises 4 chiral carbon atoies, so the compound of highly desirable synthesis enantiomer-pure.Therefore,
It is modified so that the route of synthesis synthesizing this complicated molecule more easily is popular.
Described 2 (S), 4 (S), 5 (S), 7 (S)-2,7-dialkyl group-4-hydroxyl-5-amino-8-aryl-caprylyl amide spreads out
Biology is to have feritin inhibitory activity and therefore can be used for any one of medicinal compound, and it includes such as special at US
Compound disclosed in profit 5,559,111.Up to now, the most to various preparations 2 (S), 4 (S), 5 (S), 7
(S) method of-2,7-dialkyl group-4-hydroxyl-5-amino-8-aryl-caprylyl amide derivatives is described.
In EP-A-0678503, delta-amino-gamma-hydroxyl-ω-aryl-alkane Methanamide is described, this change
Compound shows renin-inhibiting properties and the drug resistance Cardura that can be used as in pharmaceutical preparation.
In WO 02/02508, describe a kind of for obtaining delta-amino-gamma-hydroxyl-ω-aryl-alkane Methanamide
Multistep autofrettage, the most important intermediate is 2,7-dialkyl group-8-aryl-4-octenoic acid or 2,7-dialkyl group-8-aryl-
4-octene acid esters.Meanwhile, under the conditions of halo-lactonize, by the double bond halogenation of this intermediate and on 4-position on 4/5
By its hydroxylating.This halo lactone is changed into hydroxy-lactone, then, this hydroxyl is changed into a kind of leaving group, should be from
Go group azide to replace, by this amide, then this azide is changed into amine groups.
The preparation relating to 2-alkyl-5-halo amyl-4-zinecarboxylic acid ester WO02/092828, relate to 2-alkyl-5-halo
The WO 2001/009079 of the preparation of amyl-4-zinecarboxylic acid, relate to 2,7-dialkyl group-4-hydroxyl-5-amino-8-aryl caprylyl acyl
The WO 02/08172 of the preparation of amine, relate to the WO 02/02500 of 2-alkyl-3-phenylpropionic acid and relate to 2-alkyl-3-phenyl third
The WO02/024878 of alcohol describes other preparations for manufacturing delta-amino-gamma-hydroxyl-ω-aryl-alkane Methanamide
The method of intermediate.
Another kind of acquisition delta-amino-gamma-hydroxyl-ω-aryl-alkane Methanamide is disclosed in EP-A-1215201
Approach.In GB-A-0511686.8, also disclose that and obtain delta-amino-gamma-hydroxyl-ω-aryl-alkane with pyrrolidine intermediate
The another kind of approach of hydrocarbon Methanamide.
Although existing method can produce required renin inhibitor, particularly 2 (S), 4 (S), 5 (S), 7 (S)-2,7-
Dialkyl group-4-hydroxyl-5-amino-8-aryl-caprylyl amide derivatives, but remain a need for a kind of selective acquisition
These 2 (S), 4 (S), 5 (S), the conjunction of 7 (S)-2,7-dialkyl group-4-hydroxyl-5-amino-8-aryl-caprylyl amide derivatives
One-tenth approach is to guarantee can manufacture these compounds in a simple and efficient manner.
The general introduction of the present invention
It has now been surprisingly found that by novel C-8 lactams lactone compound, particularly 5-(5-oxo-four
Hydrogen-furan-2-base) pyrrolidin-2-one compounds as parent material, can with high diastereo-isomerism and enantiomeric purity and
Economic mode obtains renin inhibitor, particularly 2 (S), 4 (S), 5 (S), 7 (S)-2, and 7-dialkyl group-4-hydroxyl-5-amino-
8-aryl-caprylyl amide derivatives.Particularly find, by using C-8 lactams lactone compound, particularly 5-(5-oxygen
Generation-tetrahydro-furan-2-base) pyrrolidin-2-one compounds is as chiral building block and introduces organic aromatics when end of synthesis
Part, the art methods that the method introduces organic aromatic moiety in early days in frame structure than at composition sequence is more effective.
Additionally, utilize C-8 lactams lactone compound to lock and maintain spatial chemistry easily, and therefore, simplifying preparation should
The method of class complicated molecule.
Detailed description of the invention
Therefore, in first aspect, the present invention relates to the compound or its salt of formula (II)
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl；And
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
Person is by C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen institute is single-, two-or three-replace and/
Or replaced by trifluoromethyl.
In a preferred embodiment, R3It is C1-7Alkyl, preferably side chain C3-6Alkyl, most preferably isopropyl
Base.
In a preferred embodiment, R4It is C1-7Alkyl, preferably side chain C3-6Alkyl, most preferably isopropyl
Base.
The compound of formula (II) preferably has a following spatial chemistry:
The compound of formula (II) most preferably has a structures below:
The compound of formula (II) can be especially useful for synthesizing the material of pharmaceutical active, preferably renin inhibitor such as A Liji
Logical sequence, material the most as described below.
Present inventors have found that preparation formula (II) key intermediate facilitate method, will be below to it
It is described in detail.Any step in these reactions steps (independent or proper combination) can be used to obtain formula (II)
Compound.Additionally, at renin inhibitor, under can be individually or to use with the form of proper combination in the synthesis of aliskiren
Any step in the reactions steps of face.
Therefore, one aspect of the present invention relates to the method that one prepares above-mentioned formula (II) compound, and described method includes it
Middle R3And R4The compound or its salt hydrogenation of definition formula (I) as described in the compound of formula (II), thus by its azide portion
Divide and change into amine and complete the Guan Bi of lactam nucleus.
This process step itself also form one embodiment of the invention.
R3And R4Preferred embodiment can derive from the definition of formula (II) compound.The compound of formula (I) preferably has
There is a following spatial chemistry:
The compound of formula (I) can obtain by method well-known in prior art, particularly can be according to EP-A-
The method preparing compound III in 0678514 (which is incorporated herein by reference), particularly such as its process embodiment, especially
It is method disclosed in embodiment 2, particularly obtains by the method converting 2.c1.
Or, the compound of formula (II) can be prepared with from adjuvant used different auxiliary agent in formula (I) compound.
Therefore, on the one hand, the present invention relates to the method that one prepares above-mentioned formula (II) compound, described method include by
Wherein R3And R4Definition as described in the compound of formula (II) and Aux* is to form the auxiliary agent of ester or amide with carbonyl functional group
The compound or its salt hydrogenation of formula (I '), thus its azide is partially converted into amine and completes lactam nucleus Guan Bi.
This process step itself also form one embodiment of the invention.
The preferred embodiment of Aux* include ephedrine compound,Oxazolidone analog, crassitude keto analog, carbon
Hydrate analog and cyclic alcohol or amine.Typical example include these materials described below with and the like, especially
It isOxazolidone analog, such as Evans auxiliary agent or in a most general sense, the alpha-substituted of chiralityOxazolidone analog.
Mentioned below for preparing the document of these auxiliary agents and it being described in more detail.Compound except formula (I)
In outside used Evans auxiliary agent, preferably Herba Ephedrae alkaline auxiliary agent and ring-type alcohol type auxiliary agent as (+)-fenchol.
The compound of formula (I ') can be grasped according to the experiment for Evans auxiliary agent as summarized in EP-A-0 678 514
Make to be prepared.Therefore, by wherein R3Definition formula as described in the compound of formula (II) (I ' i) shown in suitable
Acid chloride such as 3-methyl-butrylamino chlorine
Or there is suitable alkali in the Aux*-H that the definition of its salt and wherein Aux* is as described in the compound of formula (I ')
In the case of react, thus obtain the compound of formula (I ' ii)
Similarly, this reaction can be with wherein R4The acyl group of definition formula as described in the compound of formula (II) (I ' iii)
In the definition of chlorine or its salt and wherein Aux* Aux*-H as described in the compound of formula (I ') in the case of there is suitable alkali
Carry out,
Thus obtain the compound of formula (I ' iv)
Can also be by the bromo-but-2-ene of (E)-1,4-two of the compound of formula (I ' ii) and (I ' iv) and formula (I ' v)
React in the case of there is highly basic, thus obtain the compound or its salt of formula (I ' vi)
Wherein R3And R4Definition as described in the compound of formula (II) and the definition of Aux* is as described in the compound of formula (I ').
If R3And R4Identical, i.e. R3=R4, then it should be recognized that by the compound of the formula of 2 or more equivalents (I ' ii) and formula
The bromo-but-2-ene of (E)-1,4-two of (I ' v) reacts.
Therefore, the compound or its salt of formula (I ' vi)
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace；And
Aux* is to form the auxiliary agent of ester or amide with carbonyl functional group;
It is to prepare renin inhibitor such as the valuable intermediate in the method for aliskiren in an efficient way.Therefore,
This compounds and obtain the method for compound (II) with this intermediate (I ' vi) and also form an enforcement of the present invention
Scheme.
With halo lactone reaction condition by the compound of formula (I ' vi) further with halogenating agent such as NCS, NBS, NIS (all
For N-halosuccinimides), Br2Or bromo hydantoin (bromohydantoin) reacts, thus formed formula (I '
Vii) compound or its salt,
Wherein R3And R4Definition as described in the compound of formula (II), the definition of Aux* as described in the compound of formula (I ') and
Hal is halogen.
Then, by with N3 -Source converts and the halogen functional group of formula (I ' vii) compound changes into azide, thus
Compound to formula (I ').N3 -The example in source includes standard reagent such as LiN3、NaN3、KN3、MeN3, (alkyl)4NN3Or (alkyl)3NHN3The alkylammonium azide of type such as tetraalkyl guanidine azide or organic metal azide.This reaction is in this area
Technical staff it is known that under conditions of such as mix at homogeneous or two-phase solvent mixture or ion type liquid or ion type liquid
Compound is carried out.This reaction is preferably at 0 to 120 ° of C, such as 20 to 100 ° of C, carries out at a temperature of preferably 50 to 80 ° C.
The azide of formula (I) or (I ') compound is partially converted into amine and to complete the reaction of lactam nucleus Guan Bi preferred
Ground is to carry out in the case of the integrity of other functional group that can keep on this molecule.Hydrogenation is typically being deposited
Selected from heterogenous catalyst or the catalyst of homogenous catalyst agent, such as Wilkinson ' s catalyst, the preferably feelings of heterogenous catalyst
Carry out under condition.The example of catalyst includes Raney nickel, palladium/C, Pd (OH)2(Perlman ' s catalyst), nickel borides, platinum
Or platinum metal oxides, rhodium, ruthenium and zinc oxide, more preferably palladium/C, platinum or platinum metal oxides, most preferably
Palladium/C.The consumption of described catalyst is preferably 1 to 20%, and more preferably 5 to 10%.This reaction can be in atmospheric pressure or rising
Pressure such as 2-10 bar, such as carry out under the pressure of 5 bars, this reaction is more preferably under atmospheric pressure carried out.This hydrogenation is excellent
Selection of land is carried out in atent solvent, more preferably carries out in oxolane or toluene.Proton solvent is also applicable
, such as alcohol, such as ethanol or methanol or ethyl acetate.These solvents can be applied in presence of water.Selected
Response time and temperature should make this reaction can be in the case of not producing unwanted by-product within the shortest time
Complete.This reaction typically extremely refluxes at 0 DEG C, preferably 0 to 60 DEG C, such as 0 to 40 DEG C, and more preferably 15-30 DEG C, as carried out under room temperature
10 minutes to 12 hours, preferably 20 minutes to 6 hours, most preferably 30 minutes to 4 hours, such as 1 to 3 hour or 6 to 12 hours.
During the hydrogenation of compound (I) or (I '), protonation auxiliary agent A ux*-H of stoichiometric, asOxazolidine
Ketone, i.e. chiral auxiliary (such as (S)-Evans reagent) are split off.Since compound (II) and auxiliary agent, such as described Evans auxiliary agent all
It is crystalline and there is similar character, therefore, it can by simple isolation technics (crystallize or extract) two kinds of chemical combination
Thing carries out separating and simultaneously by the auxiliary agent recycling of this costliness.Find by the lactonic ring soap by lactams lactone (II)
Change, it can be made because lactonic ring is opened to transfer in aqueous phase, andOxazolidone (or sensu lato auxiliary agent) has rested on
Machine mutually in.Being separated by simple, be then acidified aqueous phase, can lactonize again, it allows to isolate
Pure compound (II).Saponification is preferably by with alkali such as organic base or inorganic base, and preferably inorganic base has been processed to.
The example includes LiOH or NaOH.Described saponification is typically carried out in suitable solvent.The example include aqueous system or
Aqueous/ORGANIC SOLVENT MIXTURES and even organic solvent such as alcohols or toluene, and preferred alcohols/aqueous mixtures, such as ethanol/water
Solution.After carrying out being separated, generally by aqueous phase acidifying with by γ-hydroxy-acid salt protonation and the γ-hydroxyl of acquisition free form
Base acid.But the selected typical acid being applicable to described acidifying is that acidity is more higher than the acidity of γ-hydroxy acid can retain this
The acid of the integrity of other functional group on molecule.Suitable acid includes organic acid, such as citric acid, tartaric acid or similar acid,
Or the dilutest HCl of diluted mineral acid.Described free acid will re-form lactone (II), preferably by being heated to by this mixture
Such as 30 to 80 DEG C, more preferably 40 to 60 DEG C, as 50 DEG C re-form lactone (II).
Therefore, the compound or its salt of formula (II ')
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl；With
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace;
It it is the valuable intermediate of the method preparing renin inhibitor such as aliskiren in an efficient way.Therefore, should
Compounds and obtain the method for compound (II) with this intermediate (II ') and also form one embodiment of the present invention
Case.
Compound (II) preferred embodiment be also compound (II ') institute preferably.Three-dimensional the most below
Learn:
Described compound preferably has following formula
As a kind of selective method of acquisition formula (II) compound, another aspect of the present invention relates to one and prepares above-mentioned
The method of the compound of formula (II), described method includes wherein R3And R4Definition formula as described in the compound of formula (II)
(III) compound or its salt processes,
Thus convert it into wherein R3And R4Definition as described in the compound of formula (II) and R6It is C1-7Alkyl or C3-8Ring
The anhydride of the formula (IV) of alkyl or its salt；
Its acidic moiety is activated, is then hydrogenated, thus its azide is partially converted into amine and completes interior acyl
Amine ring closes.The compound of this process step itself and formula (IV) also form one embodiment of the invention.
R3And R4Preferred embodiment can derive from the definition of formula (II) compound.
In a preferred embodiment, R6It is C1-7Alkyl, more preferably straight or branched C1-4Alkyl, most preferably
Ground is methyl, ethyl, isopropyl or isobutyl group.
The compound of formula (IV) preferably has a following spatial chemistry:
The compound of formula (III) can obtain by the well-known method of prior art, particularly can be according to preparation
The method of this compounds in EP-A-0 678 514 (which is incorporated herein by reference), particularly such as its processing and implementation
Example, the especially method described in embodiment 3 are obtained by the compound of formula as defined above (I).It is likewise possible to according to
The compound of formula (I ') is converted the compound of an accepted way of doing sth (II) by these operations.
Two kinds of conversions can be with the form of independent process by separating the anhydride of formula (IV) or not carry out point
From one pot type synthesis (one-pot synthesis) form be processed to carry out to it.After the anhydride forming formula (IV),
Preferably directly the reactant mixture obtained is hydrogenated.
The reaction of formula (III) compound for forming the mixed acid anhydride of formula (IV) thus activated by its acid moieties is more preferably
Ground is to carry out under conditions of the integrity of other functional group that can keep on this molecule.Generally with the acid being activated, as
Acid chloride R6-CO-Cl introduces described anhydride.It is added thereto to the acid being activated the most over a period to come.This reaction is excellent
Selection of land is under basic or acidic conditions, more preferably carries out in the basic conditions.Suitable alkali includes organic or inorganic
Alkali, preferably organic base, more preferably nitrogen base, even more preferably from tertiary nitrogen alkali.The example of tertiary nitrogen alkali includes trimethylamine, DBU, triethylamine and two
Diisopropylethylamine.This reaction can be carried out in any suitable solvent, preferably at proton solvent such as ether, particularly THF
Carry out with in TBME, aromatics or halogenated solvent, more preferably THF or toluene.Selected response time and temperature make this reaction
Can complete within the shortest time in the case of not producing any unwanted by-product.This reaction is typically at-20 DEG C extremely
Backflow, more preferably 0-30 DEG C, is carried out 1 minute to 12 hours at 0 to 10 DEG C by preferably-10 to 40 DEG C, and preferably 10 minutes little to 4
Time, most preferably 15 minutes to 2 hours, such as 30 minutes to 1 hours.Refer to standard operation well known to the skilled person
And such as at Houben-Weyl, the E5/2 volume (1985), the 934-1183 page, Houben-Weyl, the E5/1 volume (1985),
The 193-773 page, and Houben-Weyl, volume 8 (1952), it is described by 359-680, it is here drawn
Enter as reference.
For its azide being changed into amine and completing the reaction of formula (IV) compound that lactam nucleus closes preferably
It is to carry out under conditions of the integrity of other functional group on this molecule can keep.Hydrogenation is typically to exist selected from heterogeneous
Catalyst or homogenous catalyst agent, such as Wilkinson ' s catalyst, preferably carried out in the case of heterogenous catalyst.Catalyst
Example include Raney nickel, palladium/C, Pd (OH) 2 (Perlman ' s catalyst), nickel borides, platinum or platinum metal oxides, rhodium,
Ruthenium and zinc oxide, more preferably palladium/C, platinum or platinum metal oxides, most preferably palladium/C.The consumption of described catalyst is preferred
Ground is 1 to 20%, more preferably 5 to 10%.This reaction can be at atmospheric pressure or the pressure of rising, such as 2-10, the such as pressure of 5 bars
Carrying out under power, this reaction is more preferably under atmospheric pressure carried out.Described hydrogenation is preferably carried out in atent solvent,
More preferably carry out in oxolane or toluene.Selected response time and temperature make this reaction not producing
Complete within the shortest time in the case of raw any unwanted by-product.This reaction typically extremely refluxes at 0 DEG C, and preferably 0
To 40 DEG C, more preferably 15-30 DEG C, as carried out under room temperature 30 minutes to 48 hours, within preferably 2 hours, to 36 hours, most preferably enter
Row 12 minutes to 24 hours, such as 17 to 23 hours.
As the method that the another kind obtaining formula (II) compound is selective, another aspect of the present invention relates to one and prepares
The method of formula defined in face (II) compound, described method includes wherein R3And R4The compound institute of definition such as formula (II)
The compound or its salt of the formula (III) stated processes,
Convert it into wherein R3And R4Definition as described in the compound of formula (II) and R7It is C1-7Alkyl or C3-8Cycloalkyl
The ester of formula (V) or its salt；
Then by hydrogenation, its azide it is partially converted into amine and completes lactam nucleus and close.This process step is originally
The compound of body and formula (V) also form one embodiment of the invention.
R3And R4Preferred embodiment can derive from the definition of formula (II) compound.
In a preferred embodiment, R7It is C1-7Alkyl, more preferably straight or branched C1-4Alkyl, most preferably
Ground is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or isobutyl group.
The compound of formula (V) preferably has a following spatial chemistry:
The compound of the formula (III) that can be used as the parent material of this conversion can obtain as described above.
Two kinds of conversions can be carried out by separating the ester of formula (V) with the form of independent process, or not carry out point
From one pot type synthesis form carry out.Preferably directly the reactant mixture obtained after forming the ester of formula (V) is carried out hydrogen
Change.
Preferably other can be being kept on this molecule for forming the reaction of formula (III) compound of the ester of formula (V)
Carry out under conditions of the integrity of functional group.Described ester is typically by with suitable solvent such as SOCl2Acid (III) is converted
Become the acid being activated, as acid chloride is introduced into.Or, can be in a fast and efficient manner by with suitable R7-three nitrogen
Alkene introduces described ester as alkyl donor, produces nitrogen simultaneously.The example of triazenes include aryltriazenes such as 3-methyl isophthalic acid-
(p-tolyl)-triazenes.This reaction is carried out preferably in neutral conditions.This reaction can be at any suitable solvent
In carry out, described solvent preferred proton solvent such as ether, such as THF or TBME, aromatics or halogenated solvent, more preferably THF, dichloromethane
Or toluene.Selected response time and temperature make this reaction can in the case of not producing any unwanted by-product
Complete in the shortest time.This reaction typically extremely refluxes at 0 DEG C, preferably 10 to 40 DEG C, more preferably 15-30 DEG C, under room temperature
Carry out 1 minute to 12 hours, preferably 10 minutes to 6 hours, most preferably carry out 30 minutes to 4 hours, such as 2 to 3 hours or straight
To stopping any nitrogen of generation.Such as, at Organicum, Wiley-VCH, Ed.20, to some by carboxylic in page (1999) the 442nd
Processed with acid is described for other method of ester, and which is incorporated herein by reference.
Its azide is partially converted into amine and completes the reaction of formula (V) compound that lactam nucleus closes preferably
Can keep carrying out under conditions of the integrity of other functional group on this molecule.Hydrogenation is typically to urge selected from heterogeneous in existence
Agent or homogenous catalyst agent, such as Wilkinson ' s catalyst, preferably carried out in the case of heterogenous catalyst.The reality of catalyst
Example includes Raney nickel, palladium/C, Pd (OH)2(Perlman ' s catalyst), nickel borides, platinum or platinum metal oxides, rhodium, ruthenium
And zinc oxide, more preferably palladium/C, platinum or platinum metal oxides, most preferably palladium/C.The consumption of described catalyst is excellent
Selection of land is 1 to 20%, more preferably 5 to 10%.This reaction can be at atmospheric pressure or the pressure of rising, such as 2-10, such as 5 bars
Carrying out under pressure, this reaction is more preferably under atmospheric pressure carried out.Described hydrogenation is preferably carried out in atent solvent
, more preferably carry out in oxolane or toluene.Selected response time and temperature make this reaction can be not
Complete within the shortest time in the case of producing any unwanted by-product.This reaction is typically 0 DEG C of extremely backflow, preferably
0 to 40 DEG C, more preferably 15-30 DEG C, as carried out under room temperature 30 minutes to 48 hours, within preferably 2 hours, to 36 hours, most preferably enter
Row 12 to 24 hours, such as 17 to 23 hours.
The distinct methods obtaining formula (II) compound is described by following flow process 1:
Flow process 1: obtain the approach of the C-8 lactams lactone of formula (II)
Flow process 1 is illustrated using Evans auxiliary agent as auxiliary agent, but can also use such as institute in compound (I ')
Other auxiliary agent of general introduction.Therefore, it can by implementing obtaining as described in flow process 1 with the compound of formula (I ') as parent material
Obtain the identical approach of the C-8 lactams lactone of formula (II).
In presently preferred embodiment, this synthesis includes as another step or is separately synthesized
Wherein R3And R4Definition as described in the compound of formula (II) and Act is selected from amido protecting group, particularly carbamate
The preparation of formula (VI) compound or its salt of activated group；
Described activated group is introduced on the nitrogen of its compound or its salt being included in formula (II).This process step itself with
And the compound of formula (VI) also form some embodiments of the present invention.
This conversion be carry out at the standard conditions and at such as standard reference works, such as J.F.W.McOmie, " have
Blocking group (Protective Groups in Organic Che-mistry) in chemical machine ", Plenum Press, human relations
Honest and New York, 1973, T.W.Greene and P.G.M.Wuts, " blocking group (the Protective Groups in organic synthesis
In Organic Synthesis) ", the 3rd edition, Wiley, New York 1999, " peptides (The Peptides) ";Volume 3 (editor:
E.Gross and J.Meienhofer), Academic Press, London and New York 1981, " Methoden der orga-
Nischen Chemie " (method (Methods of Organic Chemistry) in organic chemistry), Houben Weyl,
4th edition, the 15/I volume, Georg Thieme Verlag, Stuttgart 1974, H.-D.Jakubke and H.Jeschkeit, ", Peptide, Proteine " (aminoacid, peptides, albumen (Amino acids, Peptides,
), Proteins) Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982 and Jochen
Lehmann, " Chemie derKohlenhydrate:Monosaccharide und Derivate " (carbohydrate chemistry:
Monosaccharide and derivant (Chemistry of Carbohydrates:Monosaccharides and Derivatives)),
Georg Thieme Verlag, is described it in Stuttgart 1974, and these works are incorporated herein by ginseng
Examine.
When Act is alkoxy carbonyl thus forms a kind of carbamate, this reaction is particularly preferred that at alkalescence bar
Carry out under part.Alkali used is stoichiometric or catalytic amount.Suitable alkali includes organic or inorganic base, the most organic
Alkali, more preferably nitrogen base, even more preferably from tertiary nitrogen alkali.The example of tertiary nitrogen alkali includes triethylamine, diisopropyl ethyl amine, DBU, TMEDA
And trimethylamine.Can be with DMAP as catalyst.This reaction can be carried out in any suitable solvent, the preferred pole of described solvent
Property solvent such as ethyl acetate or isopropyl acetate, ether, such as THF or TBME or halogenated solvent, more preferably THF, dichloromethane or second
Isopropyl propionate.Selected response time and temperature make this reaction can be in the case of not producing any unwanted by-product
Complete within the shortest time.This reaction typically extremely refluxes at 0 DEG C, preferably 0 to 60 DEG C, more preferably 15-50 DEG C, such as 20-45
Carry out at DEG C 10 minutes to 36 hours, preferably 3 hours to 24 hours, most preferably carry out 6 hours to 24 hours, as 12-17 is little
Time.
Another important embodiment of the present invention relates to the compound or its salt of formula (VI),
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace；With
Act is the activated group selected from amido protecting group, particularly carbamate.
In another preferred embodiment, Act is acyl group or the sulfonyl being replaced.
In a preferred embodiment, R3It is C1-7Alkyl, preferably side chain C3-6Alkyl, most preferably isopropyl
Base.
In a preferred embodiment, R4It is C1-7Alkyl, preferably side chain C3-6Alkyl, most preferably isopropyl
Base.
In a preferred embodiment, Act is N-protected group, such as, in chemistry of peptides, especially enter pyrrolidine
Amido protecting group conventional in the chemistry of row protection (see: " blocking group in organic synthesis ", the 5th edition,
T.W.Greene&P.G.M.Wuts, which is incorporated herein by reference).Below, in order to unanimously, tie up in composition sequence
Hold use term " Act ".It should be recognized that when being present on lactams nitrogen, " Act " is as activated group and at interior acyl
After amine ring is opened, Act group is a kind of blocking group.
Preferably blocking group includes that such as (i) is by phenyl, as single-, two-in benzyl or trisubstituted C1-C2-alkyl, (or)
Benzhydryl or trityl, wherein said phenyl is unsubstituted or one or more, such as two or three residue examples
As selected from C1-C7-alkyl, hydroxyl, C1-C7-alkoxyl, C2-C8-alkanoyloxy, halogen, nitro, cyano group and CF3Residue taken
Generation；Phenyl-C1-C2-alkoxy carbonyl；With pi-allyl or cinnamyl.Especially preferably benzyloxycarbonyl (Cbz), 9-fluorenyl first
Epoxide carbonyl (Fmoc), benzyloxymethyl (BOM), oxy acid methyl neopentyl (POM), tri-chloroethoxy base carbonyl (Troc), 1-gold
Just alkoxy carbonyl (Adoc), but can also be benzyl, cuminyl (cumyl), benzhydryl, trityl, pi-allyl,
C1-10Alkenyloxycarbonyl groups, such as allyloxy carbonyl.Described blocking group can also is that silicyl, such as trialkylsilyl
Base, especially trimethyl silyl, tert-butyl-dimetylsilyl, triethylsilyl, triisopropyl monosilane
Base, trimethylsilylethoxymethyl (SEM), and can also is that sulfonyl (the such as C being replaced1-C7-alkyl, virtue
Base such as phenyl, the aryl being replaced are as by C1-C7-alkyl, halo, hydroxyl replace or C1-C7The substituted phenyl of-alkoxyl, especially
It is that (aryl being replaced is sub-for tosyl (4-methylphenyl sulfonyl) or camphor sulfonyl or the sulfinyl that is replaced
Sulfonyl).For the application of sulfonyl and acyl group, D.Savoia et al., J.Org.Chem. can be referred to,54,228
(1989) and wherein cited document.
The example of Act includes C1-10Alkenyloxycarbonyl groups, C6-10Aryl-C1-6Alkyl and C1-6Alkyl-carbonyl, C6-10Virtue
Base-carbonyl, C1-6Alkoxy-carbonyl, C6-10Aryl-C1-6Alkoxy carbonyl, C1-6Alkyl-sulfonyl base or C6-10Aryl-sulfonyl,
Such as C1-10Alkenyloxycarbonyl groups, C6-10Aryl-C1-6Alkyl and C1-6Alkyl-carbonyl, C6-10Aryl-carbonyl, C1-6Alkoxyl-carbonyl
Base and C6-10Aryl-C1-6Alkoxy carbonyl.In a preferred embodiment, Act is C6-10Aryl-C1-6Alkoxyl carbonyl
Base, C1-6Alkoxy-carbonyl, allyloxy carbonyl or C6-10Aryl-C1-6Alkyl such as benzyl, t-butoxy carbonyl or benzyloxy
Carbonyl.In a preferred embodiment, Act is t-butoxy-or benzyloxycarbonyl.
The compound of formula (VI) preferably has a following spatial chemistry:
The compound of formula (VI) more preferably has a structures below:
The compound of formula (VI) most preferably has a structures below:
The compound of formula (VI) can be especially useful for synthesizing pharmaceutically active substances, preferably renin inhibitor such as aliskiren,
Synthesize as the most as described below.
In presently preferred embodiment, this synthesis includes as other step or is separately synthesized
Wherein R3And R4Definition as described in the compound of formula (II) and Act is selected from amido protecting group, particularly carbamate
Activated group, R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl;R2
It is halogen, hydroxyl, C1-4Alkyl or C1-4The preparation of the compound or its salt of the formula (VIII) of alkoxyl；
Lactams lactone that it N-including opening formula as defined above (VI) with the compound of formula (VII) is activated or
The step of the lactam nucleus of its salt,
Wherein Y is a kind of group comprising metal such as-Li ,-MgX ,-magnesates, aryl magnesium class such asWherein the definition of R1 and R2 is as described herein,
Alkyl magnesium class, such as side chain C1-7Alkyl-Mg-,-MnX, (alkyl)3MnLi-or-CeX2(wherein X is halogen such as Cl, I
Or Br, more preferably Br);And R1And R2It is as defined above described in the compound of face formula (VIII).This process step itself with
And compound (VIII) and (VII) also form some embodiments of the present invention.For this conversion, it is also shown in
D.Savoia et al., J.Org.Chem.,54, 228 (1989) and wherein cited document.
For the compound of formula (VIII), R3、R4Formula (VI) chemical combination can be derived from the preferred embodiment of Act
The definition of thing.
In a preferred embodiment, R1It is hydroxyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6
Alkyl, more preferably C1-4Alkoxy-C1-4Alkoxyl, most preferably methoxy propoxy.
In a preferred embodiment, R2It is hydroxyl or C1-4Alkoxyl, more preferably side chain C1-4Alkoxyl,
Preferably methoxyl group.
The compound of formula (VIII) preferably has a following spatial chemistry:
The preferred embodiment of formula (VIII) compound has a following formula:
The compound of formula (VII) can be obtained by the compound of formula (VII '), obtains the most on the spot:
Wherein X is halogen such as Cl, I or Br, more preferably Br;And R1And R2It is as defined above the compound of formula (VIII)
Described.
The compound of formula (VII) can be prepared according to method well known to the skilled person, particularly
Can be according to halogen metal swap operation, such as can be more as described herein below described in the literature references of distinct methods
As be prepared:
Lit.1: for magnesates:
A) K.Oshima et al., Angew.Chem., Int.Ed.2000,39, 2481 and wherein cited document.
B) K.Oshima et al.;J.Organomet.Chem., 1999,575,1-20.
C) K.Oshima et al., J.Org.Chem.,66,4333(2001);
D) A.Akao et al., Tetrahedron Lett.,47,1877(2006);
E) K.Ishihara et al., Org.Lett.,7, 573 (2005) report trialkyl MgLi magnesates to carbonyl
The addition of base;
F) T.Mase et al., Tetrahedron Lett., 42,4841 (2001).
Lit.2: for Grignard reagent:
A) P.Knochel et al., Angew.Chem.Int.Ed 2000,39,4414
B) P.Knochel et al., Angew.Chem.Int.Ed.2003,42,4438
C) Houben-Weyl, the 13/2a volume, the 53-526 page
D) P.Knochel et al.;Synthesis 2002,565,
E) P.Knochel et al., Angew.Chem.,118, 165 (2006), the diaryl Mg compound of electron rich
F) S.Hall et al., Heterocycles,24, 1205 (1987), the direct Li-halogen exchange carried out with Li metal
g)Pat.Appl.;DE 10240262A1,2004.03.11, the direct Li-halogen exchange carried out with Li metal
h)C.Feugeas,Bull.Soc.Chim.Fr.,(8)1892-1895(1964);The Mg metal bromine to electron rich
Directly act on for aryl compound thus obtain the Mg compound of electron rich
i)C.Feugeas,Comptes Rendus,90,(1),113-116(1965);The Mg metal bromine to electron rich
Directly act on for aryl compound
J) B.Bogdanovic et al., Angew.Chem., Int.Ed.,39,4610(2000)
K) Grignard reagent handbook (Handbook of Grignard reagents) (Eds.G.S.Silverman,
P.E.Rakita) Marcel Dekker, New York, 1996
l)N.Krause,“Metallorganische Chemie”,Spektrum AkademischerVerlag,
Heidelberg, the 1996, the 3rd chapter
M) Grignard reagent new development (Grignard reagents New Developments), Ed.H.G.Richey,
John Wiley & Sons,Chichester,2000。
All these data are here incorporated by reference.
Organic metal class material (VII) is typically to make by compound (VII ') according to different documents recited above
Standby.This reaction is typically carried out in atent solvent, more preferably mixes at oxolane, other ethers or toluene or solvent
The mixture of compound such as ethers such as THF and alkane such as hexane, heptane or hexamethylene is carried out.Selected response time and temperature
Degree makes this reaction can complete within the shortest time in the case of not producing any unwanted by-product.This reaction typical case
Ground, at low temperature or in room temperature, such as 0 to 30 DEG C, is carried out at more preferably 0 to 20 DEG C.In one embodiment, described reaction is permissible
0 DEG C or lower temperature, preferably-80 to-20 DEG C, more preferably-80 to-40 DEG C, at-78 to-50 DEG C, carry out 30 minutes extremely
10 hours, preferably 1 hour to 5 hours, most preferably carry out 1.5 to 4 hours, such as 2 to 3 hours.
Special challenge in the case of compound (VIII) and metallorganic such as (VII ') react is in lactams portion
Divide the chemo-selective difference between the reaction on lactone part.By introducing activated group Act on amide nitrogen within it, this
The inventor of invention is it has been found, surprisingly, that only its lactam nucleus is opened and its lactone keeps complete.
The compound of discovery formula (VII) is important reagent in above-mentioned conversion, and therefore, in the conjunction of renin inhibitor
One-tenth is important reagent.Therefore, one aspect of the present invention further relates to the compound or its salt of formula (VII)
Wherein Y is a kind of group comprising metal such as-Li ,-MgX ,-magnesates, aryl magnesium class such asWherein the definition of R1 and R2 is as described herein, alkyl magnesium class, such as side chain C1-7Alkyl-Mg-,-MnX, (alkane
Base)3MnLi-or-CeX2, wherein X is halogen such as Cl, I or Br, more preferably Br;R1It is halogen, hydroxyl, C1-6Haloalkyl,
C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl；And R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl.
This compounds allows to be connected in described carbochain the aromatic fractions of described renin inhibitor in an efficient way.
Y is preferably Li, magnesate or MgBr, more preferably Li or MgBr, is still more preferably MgBr.Formula
(VII) compound preferably has a structures below:
In one embodiment, it is preferred to have the compound of following structure:
The compound of formula (VII ') preferably has a structures below:
After compound (VI) is changed into compound (VIII), preferably do not holding high in simply and conveniently mode
In the case of expensive purification process, compound (VIII) is separated.Post processing to compound (II) is similar, finds to pass through
The saponification of the lactonic ring of compound (VIII), owing to lactonic ring is opened it may happen that transfer in aqueous phase, and by-product
May still remain in organic facies.By being simply separated, then aqueous phase is acidified, can again lactonize,
It allows to isolate pure compound (VIII).Saponification processes preferably by or inorganic base the most organic with alkali, excellent
Selection of land has been processed in inorganic base.The example includes LiOH, NaOH, K2CO3Or Na2CO3, preferably LiOH or
NaOH.Described saponification is typically carried out in suitable solvent.The example includes that aqueous system or aqueous/organic solvent mix
Compound and even can also is that organic solvent such as alcohols or toluene, and preferred alcohols/aqueous mixtures, such as ethanol/water solution.Entering
After row is separated, generally by aqueous phase acidifying to be protonated by γ-hydroxy-acid salt, thus obtain the γ-hydroxy acid of free form.Right
The acid being applicable to described acidifying selects, and the acidity making it is stronger than described γ-hydroxy acid, but can keep again on this molecule
Other functional group, particularly Act group complete.Suitable acid includes organic acid, such as citric acid, tartaric acid, oxalic acid or class
As acid, or the dilutest HCl of diluted mineral acid.Described free acid will re-form the lactone part of compound (VIII), preferably pass through
This mixture is heated to such as 30 to 80 DEG C, more preferably 40 to 60 DEG C, as 50 DEG C re-form its lactone part.
Therefore, the compound or its salt of formula (VIII ')
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace;
R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl;
R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl;And
Act is the activated group selected from amido protecting group, particularly carbamate;
Prepare in an efficient way renin inhibitor such as the method for aliskiren in be a kind of valuable intermediate.Cause
This, this compounds and the method using this intermediate (VIII ') to obtain compound (VIII) also form the present invention's
One embodiment.
Formula (VIII ') compound particularly preferred embodiment includes salt, i.e. carboxylate.Preferably example includes that inorganic salt is such as
Alkali and alkaline earth metal ions salt, such as Li, Na, K, Mg, Ca salt, or organic salt, such as primary, secondary or tertiary amine salt.The example of primary amine includes
C3-8Cycloalkyl amine such as cyclohexylamine, primary aromatic amine, such as aniline, aromatic yl alkyl amine such as benzylamine and include aryl branched alkyl amine such as
Phenyl-or naphthyl ethyl amine.Secondary amine includes the (C of N di-substituted1-7Alkyl, C3-8Cycloalkyl, phenyl and/or phenyl-C1-4Alkyl)
Amine such as two (C1-7Alkyl) amine or hexanamine.Tertiary amine includes N tri--substituted (C1-7Alkyl, C3-8Cycloalkyl, phenyl and/or benzene
Base-C1-4Alkyl) amine.Particularly preferably Li salt.
The advantage of formula (VIII) compound using salt form is to have an opportunity to produce a kind of solid, preferred crystal, its
It preparation process is a kind of material being easier and carrying out processing.Another advantage is when C1 carbonyl is the salt of carboxylic acid and is not
During lactone a part of, the reduction carrying out C8 carbonyl can be with the wider array of reducing agent of range.
Such salt can with standard method well known in the prior art and as described embodiments as be prepared.Make
For a kind of method, this salt can be after carrying out open loop with various alkali as above to the compound of formula (VIII), directly by institute
State saponification to obtain.Or, can by the free acid alkalization of formula (VIII ') with by described γ-hydroxy-acid salt deprotonation, thus
γ-hydroxy acid to free form.Selected it is applicable to be formed the typical alkali of salt for allowing to acid is changed into salt, but
Other functional group on this molecule, the alkali of the integrity of particularly Act can be kept again.Suitable alkali includes inorganic base, as
LiOH、NaOH、Ca(OH)2、K2CO3、Na2CO3、Mg(OH)2、MgCO3, or organic base such as amine base, the most primary, secondary or tertiary amine
Alkali, the most above-mentioned alkali.
The preferred embodiment of compound (VIII) be also compound (VIII ') institute preferably.Standing below particularly preferably
Body chemistry:
Or preferably its salt, material the most as described herein.Described compound preferably has following formula
Or preferably its salt, material the most as described herein.
In presently preferred embodiment, this synthesis includes as other step or is separately synthesized
Wherein R3And R4Definition as described in the compound of formula (II), R1And R2Definition as described in the compound of formula (VIII) and Act is
Selected from the preparation of compound or its salt of the formula (IX) of the activated group of amido protecting group, particularly carbamate,
It includes the benzylic carbonyl of formula as defined above (VIII) compound is reduced into methylene moiety.This process
Step itself also form one embodiment of the invention.Similarly, this reaction can use formula (VIII ') compound or
Its salt is carried out as parent material.
R3、R4With the definition that the preferred embodiment of Act can derive from formula (VI) compound, R1And R2The side of being preferable to carry out
Case can derive from the definition of formula (VIII) compound.The compound of formula (IX) preferably has a following spatial chemistry:
Can complete by various methods to the reduction of C8 methylene moiety.Generally use hydrogenation and/or use hydride
Reduction, and in this application, when using term " reduce " in general terms, it had both included hydrogenation, included again use hydrogen
The reduction that compound is carried out.Can transformation of energy and intermediate as shown in Scheme 2.Various processes and each intermediate also form
One embodiment of the invention.
Flow process 2: obtain the approach of formula (IX) compound
Can carry out as intermediate point one-step or two-step with corresponding alcohol (X) or its salt to the reduction of compound (IX)
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace;
R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl;
R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl;And
Act is the activated group selected from amido protecting group, particularly carbamate.
Find that the compound of formula (X) is important reactant in above-mentioned conversion and is therefore in renin inhibitor synthesis
Important reactant.Therefore, one aspect of the present invention further relates to the compound of formula (X).Preferred embodiment and compound
(VIII) identical.Its alcohol functional group typically epimerism and two kinds of epimers can be separated.Formula
(X) compound preferably has a following spatial chemistry:
The compound of formula (X) more preferably has a structures below:
When using single-step method, this reaction can also be carried out through alcohol (X) (it can also be separated).By its 8
On carbonyl moiety change into the reaction of methylene functional group and preferably can keep other functional group on this molecule, especially
It is to carry out under conditions of the integrity of group Act.Carry out typically by hydrogenation to the conversion of methylene moiety.Hydrogenation is logical
It is often to exist selected from heterogenous catalyst or the catalyst of homogenous catalyst agent, carry out in the case of Wilkinson ' s catalyst
, but preferably heterogenous catalyst.The example of catalyst includes Raney nickel, palladium/C, Pd (OH)2(Perlman ' s catalyst), boron
Change nickel, platinum or platinum metal oxides, rhodium complex, ruthenium complex and zinc oxide, more preferably palladium/C, platinum or platinum
Oxide or Raney nickel, most preferably palladium/C.The consumption of described catalyst is preferably 1 to 20%, and more preferably 5 to 10%.Should
Reaction, such as 2-10 such as can be carried out under the pressure of 5 bars at atmospheric pressure or the pressure of rising, and this reaction is more preferably rising
Carry out under high pressure.Described hydrogenation is preferably carried out in atent solvent, more preferably in oxolane, first
Benzene, methanol, ethanol are carried out, and the mixture of this solvent and water can also be used.Selected response time and temperature
Degree makes this reaction can complete within the shortest time in the case of not producing any unwanted by-product.This reaction typical case
Ground, preferably 0 to 100 DEG C, more preferably 15-70 DEG C, is carried out 60 minutes to 12 hours, as 2 is little to backflow at 0 DEG C at 30-60 DEG C
Up to 6 hours.May be used without the longer response time such as 8 to 24 hours to guarantee that it converts completely.
Or, can first pass through and its carbonyl moiety be changed into alcohol (X), the most further with complex metal hydride reduction
It is reduced (hydrogenolysis), thus obtains the compound of formula (IX).
Preferably other functional group on this molecule, particularly Act group and lactone portion can be being kept to the reduction of alcohol
Carry out under conditions of the integrity divided.See Lit.:M.Larcheveque, et al., J.C.S.Chem.Commun., 83
(1985).Such reaction is well known to the skilled person and at such as Methoden der organischen
Chemie (method in organic chemistry), HoubenWeyl, the 4th edition, iv/c volume, Reduction I&II.Georg
In Thieme Verlag, Stuttgart1974, the 1-486 page being described it, it is here fully incorporated herein by
Reference.
A) R.L.Augustine, " Reduktion ", Marcel Dekker, Inc., New York, 1968,1-94,
b)F.Zymalkowski,“Katalytische Hydrierungen”,Ferdinand EnkeVerlag,
Stuttgart, 1965, the 103-114 page, 121-125,126-144
C) O.H.Wheeler, " chemistry (Chemistry of the Carbonyl group) of carbonyl ",
Ed.S.Patai, Interscience, New York, 1966, Chapter 11.
D) R.H.Mitchell et al., Tetrahedron Lett.,21,2637(1980);
E) R.T.Blickenstaff et al., Tetrahedron,24,2495(1968);
This reduction is typically to exist selected from L-Selectride, tri-alkoxy lithium aluminium hydride reduction, such as, three-t-butoxy
Lithium aluminium hydride reduction, lithium triethylborohydride (super), three-sec-butyl lithium borohydride or three n-butyl lithium borohydrides
(Lit.:A.-M.Faucher et al., Tetrahedr.Let.,39, 8425 (1998), and M.Larcheveque et al.,
J.C.S.Chem.Commun., 83 (1985)) or three-t-butoxy lithium aluminium hydride reduction, hydroboration tetraalkyl-ammonium, Zn (BH4)2With
NaBH4Suitable reducing agents in the case of or by NaBH4Middle addition lewis acid such as CeCl3Carry out.This reaction is preferred
Ground is in atent solvent, more preferably in oxolane, dichloromethane or toluene or in the mixture of these solvents
Or (in the case of water soluble substrate, use NaBH at THF/ water or ethanol/water4Or hydroboration tetra-allkylammonium) in carry out
's.Lit.:Fieser&Fieser, the XII volume, page 441 and other volume.Selected response time and temperature make this anti-
Should complete within the shortest time in the case of not producing any unwanted by-product.This reaction is typically at 0 DEG C extremely
Backflow, more preferably 20 to 80 DEG C, is carried out 1 to 48 hour at 30-60 DEG C by preferably 10 to 100 DEG C, and preferably 2 hours little to 12
Time, most preferably carry out 3 hours to 6 hours.
It follows that this alcohol (X) to be reduced further the compound of an accepted way of doing sth (IX).
This conversion to methylene moiety is carried out typically by hydrogenation.Hydrogenation is typically to urge selected from heterogeneous in existence
Agent or homogenous catalyst agent, such as Wilkinson ' s catalyst, preferably carried out in the case of heterogenous catalyst.The reality of catalyst
Example includes Raney nickel, palladium/C, Pd (OH)2(Perlman ' s catalyst), nickel borides, platinum or platinum metal oxides, rhodium, ruthenium
And zinc oxide, more preferably palladium/C, platinum or platinum metal oxides, most preferably palladium/C.The consumption of described catalyst is excellent
Selection of land is 1 to 20%, more preferably 5 to 10%.This reaction can be at atmospheric pressure or the pressure of rising, such as 2-10, such as 5 bars
Carrying out under pressure, this reaction is more preferably carried out at an elevated pressure.Described hydrogenation is preferably in atent solvent
Carry out, more preferably carry out in oxolane, ethyl acetate, toluene, methanol, ethanol, isopropanol, and can also
This solvent with the mixture of water are carried out.Selected response time and temperature make this reaction can not produce any not
Complete within the shortest time in the case of the by-product needed.This reaction is typically 0 DEG C of extremely backflow, and preferably 0 to 100 DEG C more
Preferably 15-70 DEG C, carry out 6 hours to 48 hours at 30-60 DEG C, preferably 10 hours to 36 hours, most preferably carry out 12 little
Up to 24 hours, such as 20-24 hour.
To the reduction of compound (IX) can also as described above with corresponding compound (VIII ') as parent material
Carry out, especially with its salt such as Li salt form.Preferred embodiment is described above.With mode phase disclosed above
Seemingly, this reaction can carry out using single step mode or can be through carrying out as the corresponding alcohol of intermediate (X ') or its salt
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace;
R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl;
R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl;And
Act is the activated group selected from amido protecting group, particularly carbamate.
The compound of formula (VIII ') can be according to above as the formula of parent material to the conversion of formula (X ') compound
(VIII) the method disclosed in compound and condition are carried out.Described reduction is by hydride source the most at the standard conditions
Carry out.The example of hydride source includes NaBH4、LiAlH4、LiBH4、Ca(BH4)2.Refer to document listed above money
Material.Particularly preferably complex metal hydride.These complex metal hydride typically have chiral ligand such as BINOLs, aminoacid,
Chiral amino alcohol and can with any of above hydride reagent formed complex other chiral ligand hydride reagent as above
These reagent described in face, particularly NaBH4Or LiAlH4.For preferably operation and condition, relate to:
1)Org.Proc.Res.&Dev.,4,(2),107(2000)
2)Heteroatom Chemistry,14,(7),603(2003)
3)Synth.Commun.,34,1359,(2004)
4)J.Org.Chem.,61(24),8586,(1996)
5)J.Org.Chem.,67,(26),9186,(2002)
6) Synthesis, (2), 217 (2004) and wherein cited document,
It is here incorporated by reference.
Two kinds of epimers (for syn and anti for its OH group and R3) may show different reactions
Property.Especially find that its anti-epimer is carrying out required hydrogenation with hydrogen and catalyst such as Pd/C to benzylic type OH key
In cracking, reactivity is higher.
In the superincumbent conversion of compound of discoverable type (X ') and be therefore a kind of weight in the synthesis of renin inhibitor
The reactant wanted.Therefore, an aspect of of the present present invention further relates to the compound of formula (X ').Preferred embodiment and compound
(VIII ') identical.The particularly preferably compound of formula (X ') is the salt form described in formula (VIII ') compound.Its carbinol-functional
Group is typically epimerism form and can separate two kinds of epimers.The compound of formula (X ') preferably has
There is a following spatial chemistry:
Or it is preferably its salt, as particularly as described in formula here (VIII ') compound.The compound of formula (X ') is
Preferably there is structures below:
Or it is preferably its salt, as particularly as described in formula here (VIII ') compound.
The compound of formula (X ') can be according to above as formula (X) chemical combination of parent material to the conversion of formula (IX) compound
Method and condition disclosed in thing are carried out.
In addition to the compound of formula (X) is reduced directly the compound of an accepted way of doing sth (IX), it is also possible to as shown in Scheme 2 that
The compound of formula (X) is cyclized pyrrolidine compound or its salt of an accepted way of doing sth (XI) by sample:
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace;
R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl;
R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl;And
Act is the activated group selected from amido protecting group, particularly carbamate.
Preferred embodiment is identical with compound (VIII).
Therefore, in presently preferred embodiment, this synthesis includes as other step or independence
The wherein R of synthesis3、R4、R1、R2The preparation of the compound or its salt of the formula (XI) as defined above with Act,
It includes that the benzylalcohol of compound by formula as defined above (X) and amine moiety are cyclized into pyrrolidine moiety.This
Process step itself and also form one embodiment of the invention.
R3、R4With the definition that the preferred embodiment of Act can derive from formula (VI) compound, R1And R2The side of being preferable to carry out
Case can derive from the definition of formula (VIII) compound.
Preferably it can be being kept on this molecule for forming the reaction of formula (X) compound of the pyrrolidine of formula (XI)
Carry out under conditions of the integrity of its functional group.Think during this reaction, the protonation of benzylalcohol occur, then eliminates water,
Thus obtaining benzylic carbocation, it can be by (these groups are in these conditions with Act group such as Boc-group or Cbz-group
Under be stable) be connected nitrogen-atoms intramolecular capture.Described cyclisation is typically carried out in acid condition.Suitable acid bag
Include strong organic acid or mineral acid or acid-exchange resin.Suitable strong acid preferably has < the pKa of 4.75.Preferably
Organic acid such as tartaric acid and oxalic acid or aryl or alkyl sulfonic acid, mineral acid such as Phosphoric acid or phosphonic acid or acid-exchange resin are such as
Amberlyst or Dowex, such as Dowex 50WX2-100,50WX2-200,50WX2-400, this reaction is more preferably with acid
Property ion exchange resin is carried out.When using organic acid or mineral acid, this reaction is preferably carried out in anhydrous conditions.
This reaction can be carried out in any suitable solvent, preferably at atent solvent such as aromatics or halogenated solvent, more preferably exists
Dichloromethane or toluene are carried out.Selected response time and temperature make this reaction can not produce any unwanted pair
Complete within the shortest time in the case of product.This reaction typically extremely refluxes at 0 DEG C, preferably 10 to 40 DEG C, more preferably 15-
30 DEG C, as carried out under room temperature 1 minute to 12 hours, preferably 10 minutes to 6 hours, most preferably carry out 30 minutes to 4 hours, as
2 to 3 hours.
Then, in another preferred embodiment of the present invention, by reduction or hydrogenation, the pyrrolidine of formula (XI) is turned
The compound of chemical conversion formula (IX).Therefore, in presently preferred embodiment, this synthesis includes as other
Step or the wherein R being separately synthesized3、R4、R1、R2The system of the compound or its salt of the formula (IX) as defined above with Act
It is standby,
It includes hydrogenating the pyrrolidine moiety of formula as defined above (XI) compound or reduction is so that its open loop and 8
Methylene moiety is obtained on Wei.This process step itself also form one embodiment of the invention.
Can be carried out with a step form to the conversion of compound (IX) by compound (XI) or can be corresponding to use
Pyrrolidinium (XI ') or pyrrolidine free base (XI ") carry out (see flow process 2) as two steps of intermediate or the form of multistep.
When carrying out this conversion with the form of single step, this reaction is preferably by the reduction that metal starts.Typical case used
Metal is alkali metal or alkaline-earth metal, preferably Li, Na or Ca.Such reduction is typically in liquefied ammonia or in similar reaction
Carry out under condition alkyl as is known to persons skilled in the art alcohols or low alkyl group amine and can be such as such as Houben-
Weyl, the XI/1 volume, 968-975 page, Houben-Weyl, the 4/1c volume, 645-657 page and R.L.Augustine,
" Reduktion ", Marcel Dekker, Inc., New York, 1968, " dissolving metal reduction (dissolvingmetal
Reduction) carrying out as described in ", these data are incorporated herein by.
When being obtained the compound of formula (IX) by intermediate (XI ') or (XI "), preferably pyrrolidine is hydrogenated.Hydrogen
Change is typically carried out in the case of heterogenous catalyst in existence.The example of catalyst includes Raney nickel, palladium/C, Pd
(OH)2(Perlman ' s catalyst), nickel borides, platinum or platinum metal oxides, rhodium, ruthenium and zinc oxide, more preferably palladium/
C, platinum or platinum metal oxides, most preferably palladium/C.The consumption of described catalyst is preferably 1 to 20%, and more preferably 5
To 10%.This reaction, such as 2-10 such as can be carried out under the pressure of 5 bars at atmospheric pressure or the pressure of rising, and this reaction is more preferably
Ground is under atmospheric pressure carried out.Described hydrogenation is preferably carried out in atent solvent, more preferably in oxolane, first
Benzene, alcohols such as methanol, ethanol are carried out, and the mixture of these solvents and water can also be used, most preferably use methanol,
Ethanol and the mixture of these solvents and water can also be used.Selected response time and temperature make this reaction can be not
Complete within the shortest time in the case of producing any unwanted by-product.This reaction is typically 0 DEG C of extremely backflow, preferably
0 to 100 DEG C, more preferably 15-70 DEG C, as carried out 10 minutes to 12 hours under 30-60 DEG C or room temperature, preferably 20 minutes to 6 hours,
Most preferably carry out 30 minutes to 4 hours, such as 1 to 3 hour.More details refers to Tetrahedron,54,1753
(1998).For other method, it is possible to see Houben-Weyl, the 4/1c volume, Reduktion I, the 400-405 page,
And Houben-Weyl, the XI/1 volume, the 968-975 page, it is here incorporated by reference.
During this reaction, Act group is cleaved, can come again as described in the preparation of formula (VI) compound
Enter this group.
The superincumbent conversion of compound of discoverable type (XI ') and be therefore important anti-in the synthesis of renin inhibitor
Answer thing.Therefore, one aspect of the present invention further relates to the compound of formula (XI '):
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace;
R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl;
R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl;And
X-It is a kind of anion such as halogen ion, trifluoroacetic acid root, sulfate radical, nitrate anion, oxalate, sulfonate radical, fluoroform
Sulfonate radical, phosphonate radical or phosphate radical, preferably halogen ion, trifluoroacetic acid root, sulfonate radical, phosphonate radical, phosphate radical or oxalate.
R3And R4Preferred embodiment can derive from the definition of formula (VI) compound, R1And R2Preferred embodiment can
To derive from the definition of formula (VIII) compound.
Also it is important anti-in the superincumbent conversion of compound of discoverable type (XI ") and in the synthesis of renin inhibitor
Answer thing.Therefore, an aspect of of the present present invention further relates to the compound of formula (XI "):
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace;
R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl；And
R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl.
R3And R4Preferred embodiment can derive from the definition of formula (VI) compound, R1And R2Preferred embodiment can
To derive from the definition of formula (VIII) compound.
In addition to the compound of formula (X) is reduced directly the compound of an accepted way of doing sth (IX), it is also possible to the compound of formula (X) is turned
The compound of the formula (X ") that chemical conversion is activated.Therefore, in another embodiment of the present invention, this synthesis includes as additionally
Step or the wherein R that is separately synthesized3And R4Definition as described in the compound of formula (II), R1And R2Definition such as formula (VIII)
Compound described in, Act be the activated group selected from amido protecting group, particularly carbamate and Act " be electrophilic
The preparation of the compound or its salt of the formula of group (X "),
It includes the benzylalcohol of formula as defined above (X) compound is changed into the alcohol moiety being activated.This process walks
The compound of rapid itself and formula (X ") also form one embodiment of the invention.
R3、R4With the definition that the preferred embodiment of Act can derive from formula (VI) compound, R1And R2The side of being preferable to carry out
Case can derive from the definition of formula (VIII) compound.
According to document (F.J.McQuillin, et al., J.C.S., (C), 136 (1967) and Houben-Weyl, 4/1c
Volume, page 73,379-383, activated group Act " should be electron withdraw group.Such as, trifluoroacetyl group or similar electrophilic
Group.Compared with the benzylic OH-group group not being activated, such electron withdraw group such as-CO-CF3Or-CO-CnFm(wherein Cn represents 2
To the saturated carbon chains of 8 carbon, m is 1 to 12) enhance the hydrogenation cracking of benzylic carbon-oxygen bond, the multiple of enhancing is 30-70 or more
High.Therefore, Act "-group should be Act "=-(C=O)-R9Type, wherein R9Can be alkyl, the alkoxyl-R being replaced10, virtue
Alkyl, aryl, the aryl that is replaced are (especially by EWG-substituent group such as F, CF3、NO2Or SO2Alkyl or SO2Aryl is replaced),
O-alkyl, O-aryl, NH-R10(wherein R10Can be alkyl, aryl, aralkyl, benzyl, benzoyl, substituted sulfonyl.
In the case of all, EWG part such as one or more F or CF3It should be a part for these residues.
Activated group such as Act " connection can by by (X) type compound non-proton atent solvent such as toluene,
With acyl halide or the symmetric anhydride of above-mentioned carboxylic acid or the mixed acid with other acid in THF, TBME, EtOAc, dichloromethane etc.
Acid anhydride or phosgene derivant or carbonic ester or isocyanates or phenyl isocyanate or sulfonylisocyanates carry out reaction and come
Complete.
It is then possible to the compound of formula (X ") to be converted the compound of an accepted way of doing sth (IX).Therefore, presently preferred
Embodiment in, this synthesis includes as other step or the wherein R that is separately synthesized3、R4、R1、R2Definition with Act
The preparation of the compound or its salt of formula (IX) as above,
It includes the alcohol moiety the being activated hydrogenation of formula as defined above (X ") compound or reduction, thus at 8
Upper acquisition methylene moiety.This process step itself also form one embodiment of the invention.
Can it is processed bar in mode similar in the way of the compound of formula (X) is converted an accepted way of doing sth (IX) compound
Part selects.
As another kind for the system of selection substituted, the compound of formula (X) can be carried out taking off based on free radical
Oxygen (reduces), thus obtains the compound of formula (IX).Reduction based on free radical is less prone to carry out spatial chemistry differentiation,
This is because the carbon free radical intermediates of a kind of plane would generally be produced, by it being reduced with the restructuring of hydrogen free radical.
In this case, it makes two kinds of epimers of formula (X) compound have similar reproducibility.
Therefore, in one selective embodiment of the present invention, this synthesis includes as other step or independence
The wherein R of synthesis3And R4Definition as described in the compound of formula (II) and Act is selected from amido protecting group, particularly amino first
The activated group of acid esters, R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6
Alkyl;R2It is halogen, hydroxyl, C1-4Alkyl or C1-4The preparation of formula (IX) compound or its salt of alkoxyl；
It includes that the compound of the formula (X) defined in by literary composition changes into thiocarbonyl derivative and carries out it with trip subsequently
Reduction based on base, thus obtain the compound of formula (IX).This process step itself also form of the present invention
Embodiment.
Described thiocarbonyl derivative can be any of the deoxidation being applicable to based on free radical known in the state of the art
Known thiocarbonyl derivative.Preferably example is thiocarbamate, such as imdazole derivatives, thiocarbonyls, such as Huang
Ortho esters, or sulfocarbonate.It is particularly preferably thiocarbamate or its salt of formula (XV),
Wherein R3And R4Definition as described in the compound of formula (II) and Act is selected from amido protecting group, particularly amino
The activated group of formic acid esters, R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxyl-
C1-6Alkyl;R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl.
It is important reaction in the superincumbent conversion of compound of discoverable type (XV) and in the synthesis of renin inhibitor
Thing.Therefore, an aspect of of the present present invention further relates to the compound of formula (XV).The phase of preferred embodiment and compound (VIII)
With.Its alcohol functional group typically epimerism and two kinds of epimers can be separated.The compound of formula (XV)
Preferably there is following spatial chemistry:
For benzylalcohol is to the conversion of thiocarbonyl derivative, it is possible to use method well known in the prior art.For sulfur
For carbamates, the particularly compound of formula (XV), see such as at DerekH.R.Barton and Stuart
W.McCombie,J.Chem.Soc.,Perkin Trans.1,1975, the method described in 1574, for thiocarbonyls
For xanthate, see such as Derek H.R.Barton, Doo Ok Jang, Joseph Cs.Jaszberenyi,
Tetrahedron Letters1990,31,3991;For sulfocarbonate, see such as M.J.Robins,
J.S.Wilson,J.Am.Chem.Soc.1981, 103,933 and M.J.Robins, J.S.Wilson, J.Am.Chem.Soc.1983,105,4059。
Deoxidation based on free radical is with standard method, forms institute about thiocarbonyl derivative the most in the literature
The Barton.McCombie condition stated is carried out.Bu is preferably used3SnH or three (trimethyl silyl)-silane is as also
Former dose.When with three (trimethyl silyl) silane as reducing agent, add tertiary mercaptan such as dodecyl-mercaptan as catalysis
Agent.For using the condition of three (trimethyl silyl)-silane, see such as Dietmar Schummer, Gerhard,Synlett.1990,705.Or, another kind of reducing agent, such as NaBH can be there is4In the case of use catalysis
The Bu of amount3SnBH.This reduction step can also use other silane such as phenyl silane, diphenyl silane and tri-phenyl-silane,
See such as D.H.R.Barton, P.Blundell, J.Dorchak, D.O.Jang and J.Cs.Jaszberenyi,
Tetrahedron1991, 47,8969;D.H.Barton,D.O.Jang,J.Cs.Jaszberenyi,Tetrahedron1993,49,7193.Can also be by known in the literature for the other reducing agent of deoxidation based on free radical, such as two
Alkyl phosphite, hypophosphorous acid and its salt, be shown in such as T.Sato, H.Koga, K.Tsuzuki, Heterocycles 1996,
42,499, and the 2-propanol in the case of there is dilauroyl peroxide, see such as A.Liard, B.Quicklet-
Sire,S.Z.Zard,Tetrahedron Lett.1996, 37,5877 complete required deoxidation.
Can also in the case of any intermediate not being separated with one pot type synthesis form directly by formula (VI)
Compound obtain formula (X) compound.Therefore, in one selective preferred embodiment of the present invention, this synthesis bag
Include as other step or the wherein R that is separately synthesized3And R4Definition as described in the compound of formula (II) and Act is selected from ammonia
The activated group of base blocking group, particularly carbamate, R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6
Alkyl oxy or C1-6Alkoxy-C1-6Alkyl;R2It is halogen, hydroxyl, C1-4Alkyl or C1-4The compound of the formula (X) of alkoxyl or
The preparation of its salt,
It includes the interior acyl of the lactams lactone making the N-of formula as defined above (VI) activate with the compound of formula (VII)
The step that amine ring is opened
Wherein Y is a kind of group comprising metal such as-Li ,-MgX ,-magnesates, aryl magnesium class such asWherein the definition of R1 and R2 is as described herein, alkyl magnesium class, such as side chain C1-7Alkyl-Mg-,-MnX, (alkane
Base)3MnLi-or-CeX2, wherein X is halogen such as Cl, I or Br, more preferably Br;And R1And R2It is as defined above the change of face formula (X)
Described in compound, thus obtain the compound or its salt of formula as defined above (VIII '),
Then by the benzylic carbonyl reduction of formula (VIII ') compound or its salt, thus formula as defined above (X ') is obtained
Compound or its salt, and
By the compound lactone of formula (X '), thus obtain the compound of formula (X).
This process step itself also form one embodiment of the invention.For this conversion, also can join
See D.Savoia, et al., J.Org.Chem.,54, 228 (1989) and wherein cited document.
Formula (VI), (VII), (VIII '), (X ') and the preferred embodiment of (X) compound can derive from defined over
The definition of respective compound of these compounds.Compound (VIII ') and (X ') the most in a salt form, especially
It is that the form of Li salt carries out applying.
For the compound of formula (VIII ') is to the conversion of the compound of formula (X), it is possible to use above for each conversion
Described method or the method similar to it, i.e. (include about converting to the compound of formula (VIII) from formula (VI) compound
Salt is become to convert the compound of an accepted way of doing sth (VIII ')) and it is further converted into the method described by compound of formula (X ').Right
For final step, particularly should use the compound of formula (VIII ') disclosed in when the compound of formula (X ') converts
Method, it is preferred to use mentioned here include hydride reagent such as NaBH4Or LiAlH4Hydride reduction condition, and
Wherein said complex metal hydride condition can also be used.Described free acid will form the lactone part of compound (X), preferably
By this mixture is heated to such as 30 to 80 DEG C, more preferably 40 to 60 DEG C, as 50 DEG C form lactone part.Described lactone
Change and generally can use acid condition, as used the acid bar of the such as gentleness well known in the prior art of organic acid such as citric acid
Part.
In presently preferred embodiment, this synthesis includes as other step or is separately synthesized
Wherein R3And R4Definition as described in the compound of formula (II), R1And R2Definition as described in the compound of formula (VIII) and Act is
Selected from the preparation of compound or its salt of the formula (XII) of the activated group of amido protecting group, particularly carbamate,
It includes reacting amine or its salt of the compound or its salt of formula as defined above (IX) with formula (XIII),
(the most if necessary, it is also possible to its acylamino-nitrogen is protected, then from corresponding protected formula
The compound of XII removes this blocking group).This process step itself also form one embodiment of the invention.
This conversion can be carried out according to typical peptide coupling reaction well-known in prior art, such as, can use
The method that disclosed to EP-A-678503 (which is incorporated herein by reference) method is similar is carried out, particularly
See embodiment 124 and 131, or can such as WO02/02508 (which is incorporated herein by reference), particularly its
Method disclosed in page 35 embodiments H1 (preparation of J1) is prepared.
R3、R4With the definition that the preferred embodiment of Act can derive from formula (VI) compound, R1、R2Preferred reality with Act
The scheme of executing can derive from the definition of formula (VIII) compound.The compound of formula (XII) preferably has a following spatial chemistry:
This reaction is preferably carried out under the standard conditions for being formed lactone by amide, and such as it can be suitably
Atent solvent or solvent mixture, such as at ether, in tert-butyl methyl ether, preferably in existence, there is faintly acid and weak
In the case of bifunctional catalysis's agent such as 2 hydroxy pyrimidine or proline of basic group, there is suitable alkali, such as uncle
Nitrogen base, as in the case of triethylamine at such as 0 DEG C reflux temperature to this reactant mixture of suitable temperature, such as 0 to 85 DEG C
Get off carry out.
The amide coupling with compound (XII) using above-mentioned formula (XIII) compound can also be with disclosed above
The mode that mode is similar, is carried out with the open loop analog of the compound of formula (IX).Therefore, this reaction can use corresponding formula
The compound or its salt of (IX ') is carried out as parent material,
Wherein
R3It is C1-7Alkyl or C3-8Cycloalkyl;
R4It is C1-7Alkyl, C2-7Alkenyl, C3-8Cycloalkyl, phenyl-or naphthyl-C1-4Alkyl, its most unsubstituted or
By C1-4Alkyl, O-C1-4Alkyl, OH, C1-4Alkyl amino, two-C1-4Alkyl amino, halogen and/or trifluoromethyl single-, two-or
Three-replace;
R1It is halogen, hydroxyl, C1-6Haloalkyl, C1-6Alkoxy-C1-6Alkyl oxy or C1-6Alkoxy-C1-6Alkyl;
R2It is halogen, hydroxyl, C1-4Alkyl or C1-4Alkoxyl;And
Act is the activated group selected from amido protecting group, particularly carbamate.This process step also shape itself
Become one embodiment of the invention.
The compound of formula (IX) can be with the lactonic ring of the compound of a formula (II) to the conversion of the compound of formula (IX ')
Open thus obtain the method disclosed in compound of formula (II ') and condition is carried out.Advise described amide coupling reaction it
Before, the alcohol moiety of formula (IX ') compound is protected.Chemistry is protected/deprotected to the alcohol that can use standard.
It is important reaction in the superincumbent conversion of compound of discoverable type (IX ') and in the synthesis of renin inhibitor
Thing.Therefore, an aspect of of the present present invention further relates to the compound of formula (IX ').The phase of preferred embodiment and compound (VIII ')
With.Salt form described in when the compound of formula (IX ') is particularly preferred that the compound of description formula (VIII ').The change of formula (X ')
Compound preferably has a following spatial chemistry:
Or it is preferably its salt, particularly those salt as described in civilian Chinese style (VIII ') compound.The chemical combination of formula (IX ')
Thing most preferably has a structures below:
Or it is preferably its salt, particularly those salt as described in civilian Chinese style (VIII ') compound.
The compound of formula (IX ') can be according to above as the formula (IX) of parent material to the conversion of formula (XII) compound
The method disclosed in compound and condition carry out.
It is then possible to the compound of formula (XII) to be converted the compound or its salt of an accepted way of doing sth (XIV),
Wherein R3And R4Definition as described in the compound of formula (II), R1And R2The compound institute of definition such as formula (VIII)
Stating, described conversion includes removing activated group Act;And if necessary, the free cpds of Formula X IV obtained is turned
It is melted into salt (it is preferred) or the salt obtained is changed into free cpds or its another kind of salt of Formula X IV.Such as, as
Really Act is (preferably) C1-C7-alkoxy carbonyl, such as t-butoxy carbonyl, then the removing of this group can be in normal condition
Under carry out, such as can there is acid, as in the case of halogen acids at suitable solvent, as in dioxanes such as at 0 to 50 DEG C,
Such as carry out under room temperature.The removing of Act group can be with the blocking group chemistry of standard, according to institute in following involved document
The operation stated or carry out by method well-known in prior art, see for example EP-A-0678503 (its here by
It is incorporated herein by reference), particularly embodiment 130, and optionally with such as at US-A-5,559,111 (it is here introduced into
As reference) in, the particularly reaction condition described in embodiment 83 forms salt.
The method that above-mentioned each method can be individually used for preparing renin inhibitor such as aliskiren.These steps preferably with
The united form of one or multi-step, most preferably uses with the most united form, prepares renin inhibitor such as Ah
Li Jilun.
R3、R4With the definition that the preferred embodiment of Act can derive from formula (VI) compound, R1、R2Preferred reality with Act
The scheme of executing can derive from the definition of formula (VIII) compound.Described compound most preferably aliskiren.
All these different synthesis steps and approach show, utilize the compound of formula (II) and (VI) to have discovered that ten
Point important noval chemical compound, these compounds are many possible route of synthesis, especially synthesis renin inhibitor such as synthesize Ah
Intermediate important in the approach of Li Jilun.Therefore, these formulas (II) and the compound or its salt of (VI) and its be synthetically formed
The present invention very preferred embodiment.
Set forth below is the definition of the various terms for describing the new intermediate of the present invention and synthesis step.At quilt
Time in this specification, unless in a particular case it is limited, otherwise individually or as relatively macoradical
These definition of a part (by substitute one, more than one or all general expression used or symbol be also in present disclosure
Therefore the preferred embodiments of the invention are produced) it is preferably adapted for described term.
Term " rudimentary " or " C1-C7-" define one there are most 7 and include 7, especially up to 4 and
Including the part of 4 carbon atoms, described part is side chain (branch's one or many) or straight chain and by end or non-end
End carbon is attached.Rudimentary or C1-C7-alkyl e.g. n-amyl, n-hexyl or n-heptyl, or preferably C1-C4-
Alkyl, especially methyl, ethyl, n-propyl, sec-propyl group, n-butyl, isobutyl group, sec-butyl, tert-butyl.
Halo or halogen are preferably fluorine, chlorine, bromine or iodine, most preferably fluorine, chlorine or bromine；When mentioning halo, it refers to
Be to there is one or more (the most most three) halogen atom, such as at halo-C1-C7In the case of-alkyl, such as trifluoro
Methyl, 2,2-bis-fluoro ethyl or 2,2,2-trifluoroethyl.
Alkyl preferably has most 20 carbon atoms and more preferably C1-C7-alkyl.Alkyl is straight or branched
(branch once, if or need and if possible, can be with multiple branches).Preferably methyl.
Haloalkyl can be straight or branched and preferably comprise 1 to 4 C atom, and especially 1 or 2 C is former
Son.The example has methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-
Trifluoroethyl.
Branched alkyl preferably comprises 3 to 6 C atoms.The example have i-propyl, iso-and tert-butyl and amyl group and
The branched isomers of hexyl.
Cycloalkyl preferably comprises 3 to 8 ring carbon atoms, especially preferably comprises 3 or 5 ring carbon atoms.Some examples
There are cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and ring octyl group.Described cycloalkyl optionally by one or more substituent groups, as
Alkyl, halo, oxo, hydroxyl, alkoxyl, amino, alkyl amino, dialkyl amido, sulfydryl, alkylthio group, nitro, cyano group,
Heterocyclic radicals etc. are replaced.
Alkenyl can be to comprise double bond and preferably comprise 2 to 12 C atoms, particularly preferred 2 to 8 carbon atoms straight
Chain or branched alkyl.Particularly preferably straight chain C2-4Alkenyl.Some examples of alkyl are the ethyls and third of each self-contained double bond
Base, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, myristyl, cetyl, ten
Eight alkyl (octacyl) and the isomer of eicosyl.Especially preferably pi-allyl.
Alkyl amino and dialkyl amido can be straight or brancheds.Some examples be methylamino, dimethylamino,
Ethylamino and diethylamino.
Alkoxy-alkyl epoxide can be straight or branched.This alkoxyl preferably comprises 1 to 4 and especially 1
Or 2 C atoms and described alkyl oxy preferably comprise 1 to 4 C atom.The example has methoxy epoxide, 2-first
Epoxide ethyl epoxide, 3-methoxy-propyl epoxide, 4-methoxybutyl epoxide, 5-methoxypentyl epoxide, 6-methoxyethyl
Epoxide, ethoxyl methyl epoxide, 2-ethoxyethyl group epoxide, 3-ethoxycarbonyl propyl epoxide, 4-ethoxybutyl epoxide, 5-ethoxy
Base amyl group epoxide, 6-ethoxyhexyl epoxide, propoxy methyl epoxide, butoxymethyl epoxide, 2-Among epoxide and
2-butoxyethyl group epoxide.
Alkoxyalkyl can be straight or branched.Its alkoxyl preferably comprises 1 to 4 and especially 1 or 2
C atom, and its alkyl preferably comprises 1 to 4 C atom.The example has methoxy, 2-methoxy ethyl, 3-methoxy
Base propyl group, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyethyl, ethoxyl methyl, 2 ethoxyethyl groups, 3-ethyoxyl
Propyl group, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propoxy methyl, butoxymethyl, 2-propoxyl group second
Base and 2-butoxyethyl group.
Alkoxyl can be side chain or straight chain and preferably comprise 1 to 4 C atom.The example has methoxyl group, ethoxy
Base, n-and iso-propoxyl group, n-, iso-and t-butoxy, amoxy and hexyloxy.
Blocking group (referring also under " general treatment conditions ") can be there is and it should protect related functional group not
Participate in unwanted side reaction, as being acylated, be etherified, be esterified, aoxidizing, solvolysis and similar reaction.These blocking groups
Be characterised by that it can easily i.e. be removed in the case of there is not undesirable side reaction, generally by solvolysis,
Reduction, photodissociation remove, or such as can also be removed under conditions of similar to physiological conditions by enzymatic activity, and
There are not these blocking groups in finished product.Skilled person will realize that or can readily determine that be applicable to described in context anti-
The blocking group answered.If a kind of intermediate described herein exists two or more blocking group, then can be to these
Blocking group selects, thus when needs remove one of them group, can optionally remove, such as, can make
With two or more different blocking groups that can crack at different conditions, such as one class can be another kind of by mild hydrolysis
Be hydrolyzed under severe conditions, a class is hydrolyzed in the presence of an acid, another kind of is hydrolyzed in the case of a base depositing, or
Person one being reduced property of class cracking (such as catalytic hydrogenation), another kind of is hydrolyzed.
For hydroxy-protective group, it is possible to use be applicable to hydroxyl is carried out any group of reversible protection, as " one
As treatment conditions " under standard textbook described in those blocking groups.Hydroxy-protective group is selected from (being only used as limited carrying
And several examples): silyl protecting group, especially diaryl-low alkyl group-silicyl, such as diphenyl-tert-fourth
Base silicyl, or more preferably three-low alkyl group silicyl, such as tert-butyl dimetylsilyl or trimethyl first
Silylation;Acyl group, such as low-grade alkane acidyl, such as acetyl group;Benzoyl;Elementary alkoxy carbonyl, such as t-butoxy carbonyl
(Boc) or phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl;THP trtrahydropyranyl;Unsubstituted or substituted 1-phenyl-
Low alkyl group, such as benzyl or p-methoxy-benzyl, and methoxy.Particularly preferably Boc (can be by hydrolysis by selectivity
Remove) and benzyl (can be selectively removed by hydrogenation).
For amido protecting group, it is possible to use be applicable to amino is carried out any group of reversible protection, as " one
As treatment conditions " under standard textbook described in these blocking groups.Amido protecting group is selected from (being only used as limited carrying
And several examples): the acyl group (residue of the organic carbonate being combined especially by its carbonyl or entered by its sulfonyl
The residue of organic sulfonic acid that row combines), aryl methyl, the sulfydryl being etherified, 2-acyl group-lower alkanols-1-thiazolinyl, silicyl or
N-low alkyl group pyrrolidylidene.Preferably amino-protecting groups is elementary alkoxy carbonyl, especially t-butoxy carbonyl
(Boc), phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, fluorenyl-elementary alkoxy carbonyl, as fluorenylmethoxycarbonyl groups,
2-low-grade alkane acidyl-lower alkanols-1-alkene-2-base and elementary alkoxy carbonyl-lower alkanols-1-alkene-2-base, most preferably isobutyryl
Base, benzoyl, nitrophenoxyacetyl, 4-tert-butyl nitrophenoxyacetyl, N, N-dimethylformamidinyl, N-methylpyrrolidin-
2-subunit, or especially t-butoxy carbonyl.
Unsubstituted or substituted aryl preferably has the single-or polycyclic of 6 to 22 carbon atoms, the most singly
Ring, bicyclo-or three cyclophane base section, especially phenyl (the most preferred), naphthyl (the most preferred), indenyl, fluorenyl, acenaphthylene
Base (acenapthylenyl), phenylenyl or phenanthryl, and it is unsubstituted or one or more, especially one to
Three independently selected from C1-C7-alkyl, C1-C7-alkenyl, C1-C7-alkynyl, halo-C1-C7-alkyl, such as trifluoromethyl, halogen
Element, especially fluorine, chlorine, bromine or iodine, hydroxyl, C1-C7-alkoxyl, phenoxy group, naphthoxy, phenyl-or naphthyl-C1-C7-alcoxyl
Base, C1-C7-alkanoyloxy, phenyl-or naphthyl-C1-C7-alkanoyloxy, amino, list-or two-(C1-C7-alkyl, phenyl, naphthalene
Base, phenyl-C1-C7-alkyl, naphthyl-C1-C7-alkyl, C1-C7-alkanoyl and/or phenyl-or naphthyl-C1-C7-alkanoyl)-ammonia
Base, carboxyl, C1-C7-alkoxy carbonyl, phenyloxycarbonyl, naphthoxycarbonyl, phenyl-C1-C7-alkoxy carbonyl, naphthyl-C1-
C7-alkoxy carbonyl, carbamoyl, N-be mono--or N, N-bis--(C1-C7-alkyl, phenyl, naphthyl, phenyl-C1-C7-alkyl and/
Or naphthyl-C1-C7-alkyl)-amino carbonyl, cyano group, sulfo group, sulfamoyl, N-be mono--or N, N-bis--(C1-C7-alkyl, phenyl,
Naphthyl, phenyl-C1-C7-alkyl and/or naphthyl-C1-C7-alkyl) part of-amino-sulfonyl and nitro replaced.
The officinal salt of salt especially Formula X IV compound or the general salt of any intermediate described here, in some feelings
In condition, owing to those skilled in the art are understandable chemically, do not include some salt.There is salt forming group such as alkali
In the case of property or acidic-group, can form salt, described salt such as can exist at least in part presented in dissociating
PH is in the aqueous solution of 4 to 10, or especially can in solid form, and especially crystal form is separated.
Described salt is formed the most as an acid addition salt form, preferably former by having basic nitrogen with mineral acid or organic acid
Compound or any intermediate as herein described of Formula X IV of son (such as imino group or amino) form salt, especially may be used
Medicinal salt.Suitable mineral acid has such as halogen acids, example hydrochloric acid, sulphuric acid or phosphoric acid.Suitable organic acid has such as carboxylic acid, phosphine
Acid, sulfonic acid or sulfamic acid, such as acetic acid, propanoic acid, lactic acid, fumaric acid, succinic acid, citric acid, aminoacid, such as glutamic acid or
Aspartic acid, maleic acid, hydroxymaleic acid, citraconic acid, benzoic acid, methanesulfonic acid or ethyl sulfonic acid, ethane-1,2-two sulphur
Acid, benzenesulfonic acid, 2-LOMAR PWA EINECS 246-676-2,1,5-naphthalene-disulfonic acid, N-cyclohexylsulfamic, N-methyl-, N-ethyl-or N-propyl group-ammonia
Base sulfonic acid, or other organic proton acid, such as ascorbic acid.
There is bear electric group, in the case of carboxyl or sulfo group, it is also possible to form salt with alkali, such as slaine or
Ammonium salt, such as alkali metal or alkali salt, such as sodium, potassium, magnesium or calcium salt, or with ammonia or suitable organic amine such as unitary tertiary amine,
Such as triethylamine or three (2-hydroxyethyl) amine, or heterocyclic bases, such as N-ethyl-piperidin or N, N'-lupetazin is formed
Ammonium salt.
When there is basic group and acidic-group in same a part, the compound or as herein described any of Formula X IV
Intermediate can also form inner salt.
For Formula X IV compound or generally speaking for the isolated or purified of any intermediate as herein described,
Pharmaceutically unacceptable salt, such as picrate or perchlorate can also be used.For treatment use, only use Formula X IVization
The officinal salt of compound or free cpds (may be included with in pharmaceutical preparation in the case of being suitable for), and the most at least exist
Pharmaceutically useful salt is preferably used in the case of Formula X IV compound.
In view of described compound and the free form of intermediate and salt thereof (include that these can be used as the salt of intermediate, such as
At the purification of described compound or its salt and salt used in identifying) substantial connection between form, therefore, at any time exist
When context relates to the compound of " compound ", " parent material " and " intermediate ", especially Formula X IV, suitable and convenient
And do not have clear and definite when additionally illustrating, it should be apparent that, it further relates to one or more salt or the chemical combination that dissociates accordingly
Thing, intermediate or parent material and the mixture of one or more salt, before it the most also includes any solvate, metabolism
The ester of body such as Formula X IV compound or amide, or any one of these compounds or multiple salt.Different knots can be obtained
Crystalline form, in these forms are also included within.
When compound, parent material, intermediate, salt, pharmaceutical preparation, disease, disease etc. use plural number, it refers to one
(preferably) or multiple individualized compound, salt, pharmaceutical preparation, disease, disease etc., use odd number or indefinite article (" a ",
" an ") in the case of, it is not precluded from plural number, but the most preferably only represents " one ".
Parent material Formulas I the most described here, the compound of III, VII and/or XIII, intermediate especially formula
II, II ', IV, V, VI, VIII, VIII ', IX, IX ', X, X ', X ", XI, XI ', XI ", the compound of XII and/or XV.
The above-mentioned Formula II that the invention still further relates to be carried out by its most above-mentioned precursor, II ', IV, V, VI, VIII, VIII ', IX,
IX ', X, X ', X ", XI, XI ', XI ", the synthetic method of the intermediate of XII and/or XV, including comprising production XIV compound
The single step of composition sequence, described synthesis a step more than or method in steps and/or pharmaceutically active substances, especially
Renin inhibitor, most preferably aliskiren, including single step, the described conjunction of the composition sequence comprising production XIV compound
More than the step become or method and/or pharmaceutically active substances in steps and/or it is at pharmaceutically active compound, such as feritin
Application in the synthesis of inhibitor, especially aliskiren.
General treatment conditions
According to those skilled in the art's general knowledge to limiting factor possible in single response situation, the description below is the suitableeest
For all methods described in context, likewise it is preferred that the specific reaction condition mentioned of above and below:
In any reaction described in context, suitable or in the case of needing, even if there is no specific mentioning, it is also possible to
With blocking group, the functional group being not intended to participate in given reaction is protected, and can introduce in the stage that is suitable or that need
And/or remove these blocking groups.Therefore, the reaction described in this manual does not has specific mentioning to protect and/or deprotection
In the case of, in the case of possible, also include the reaction using blocking group.
In the scope of the present disclosure, unless be illustrated within a context, it it it not the most the end of required specific Formula X IV
The group being readily removed of the component of product is referred to as " blocking group ".With described blocking group, functional group is protected
Protect, described blocking group itself and the suitable reaction introducing and removing blocking group are recorded in standard reference works, described
Works such as J.F.W.McOmie, " blocking group in organic chemistry ", Plenum Press, London and New York 1973,
T.W.Greene and P.G.M.Wuts, " blocking group in organic synthesis ", the 3rd edition, Wiley, New York 1999, " peptides ";
Volume 3 (editor: E.Gross and J.Meienhofer), AcademicPress, London and New York 1981, " Methoden der
Organischen Chemie " (method in organic chemistry), Houben Weyl, the 4th edition, the 15/I volume, Georg
Thieme Verlag, Stuttgart1974, H.-D.Jakubke and H.Jeschkeit, ",
Peptide, Proteine " (aminoacid, peptides, albumen), Verlag Chemie, Weinheim, Deerfield Beach, and
Basel1982, " blocking group ", Philip J.Kocienski, the 3rd edition, GeorgThieme Verlag, Stuttgart,
ISBN 3-13-137003-3 and Jochen Lehmann, " Chemie derKohlenhydrate:Monosaccharide
Und Derivate " (carbohydrate chemistry: monosaccharide and derivant), Georg Thieme Verlag, Stuttgart
1974, it is here incorporated by reference.The characteristic of blocking group is that it can easily (i.e. not be not intended to
Side reaction in the case of) be removed, be such as removed or (example under physiological conditions by solvolysis, reduction, photodissociation
As passed through enzymatic lysis) it is removed.Different blocking groups can be selected so that it can be in the different stages in other protection group
Group is optionally removed in the case of keeping completely.Those skilled in the art can by standard reference works above-mentioned or
The group gone out given in present specification or embodiment is readily selected out the most selective object.
All above-mentioned process steps can be at reaction condition known per se, preferably those specific reaction conditions mentioned
Under, do not exist or generally there is solvent or diluent, be preferably inertia to agents useful for same and examination used can be dissolved
In the case of the solvent of agent or diluent, there is not or exist catalyst, condensing agent or nertralizer, such as ion-exchanger,
Such as cationite, such as H+Carry out in the case of the exchanger of form, depend on reaction and/or the character of reactant, this
A little steps that process can be in reduction, the normal or temperature of rising, and e.g., from about-100 DEG C to about 190 DEG C, preferably approximately-80 DEG C to greatly
About 150 DEG C, such as, under-80 to-60 DEG C, room temperature ,-20 to 40 DEG C or reflux temperature, carry out at atmospheric pressure or in sealing container,
In the case of suitable, can carry out under elevated pressure, and/or at inert atmosphere, such as, carry out under argon or nitrogen atmosphere.
Unless illustrated in the description of described process, otherwise any specific reaction can be applicable to by wherein selecting
The solvent of solvent include these solvents of specifically mentioning, or such as can be selected from water, esters, such as lower alkyl-lower chain
Alkanoic acid esters, such as ethyl acetate, ethers, as aliphatic series ethers, such as ether or ring-type ethers, such as oxolane or two are disliked
Alkane, liquid aromatic hydro carbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1-or 2-propanol, nitrile, such as acetonitrile, halogenated hydrocarbons,
Such as dichloromethane or chloroform, amide-type, such as dimethylformamide or dimethyl acetylamide, bases, such as heterocyclic nitrogenous bases, such as
Pyridine or NMP, carboxylic acid anhydride, such as lower alkanols alkanoic acid anhydride, such as acetic anhydride, ring-type, straight or branched
Hydro carbons, such as hexamethylene, hexane or isopentane or the mixture of these solvents, such as aqueous solution.Chromatography is such as used in post processing
Or the post processing that carries out of distribution can also use such solvent mixture.In the case of needs or hope, it is possible to use nothing
Aqueous solvent.
In the case of needs, the post processing carrying out reactant mixture, especially for required compound or centre
The post processing that body carries out separating and carries out is carried out according to routine operation and step, and the most described operation and step can be unrestricted
Property ground selected from extracting, neutralize, crystallize, chromatography, evaporate, be dried, filter, be centrifuged.
The invention still further relates to wherein by office what processing stage using intermediate forms obtain compound as parent material
And carry out remain procedure of processing or wherein parent material be formed at reaction conditions or with derivant, such as to be protected
Form or salt form carry out the method for these forms applied or under described treatment conditions the method for the generation present invention obtain
Compound and method to the form that it processes in position.In the method for the invention, it is preferably used and can produce quilt
It is depicted as the parent material of preferred Formula X IV compound.Particularly preferably or phase identical with the reaction condition described in embodiment
As reaction condition.The invention still further relates to novel initial compounds as herein described and intermediate, especially can produce herein
It is referred to as those initial compounds and the intermediate of preferred compound.
The invention particularly relates to any one of method of the generation aliskiren described in context or its officinal salt.
By the following examples, the present invention is carried out non-limitative illustration, these embodiments on the other hand represent described instead
Answer the preferred embodiment of the preparation method of step, intermediate and/or aliskiren or its salt.
When being mentioned in these embodiments, " boc " represents t-butoxy carbonyl.
Embodiment:
1) the lactams lactone of formula (II) is prepared via anhydride
[3-isopropyl-5-(4-isopropyl-5-oXo-tetrahydro-furan-2-base) pyrrolidin-2-one] (IIa)
26.45g (88.9mmol) compound IIIa is dissolved in 150ml toluene.At room temperature, by 10.35g
(102.3mmol) during triethylamine is dissolved in 10ml toluene and it is at room temperature joined in the solution of parent material.Then, will
This solution is cooled to 0-5 ° of C.At such a temperature, in 25 minutes, the chlorine that 13.97g is dissolved in 10ml toluene it is added thereto to
Tetryl formate..After stirring 30 minutes at by it at 0-5 DEG C, this suspension is made to be heated up to room temperature.
This reaction vessel is transferred to hydrogenation station and there by add 5g Pd/C, 5%, Engelhard 4522
It is hydrogenated.After 21 hours, this reaction suspension is filtered.Filtrate is diluted with 150ml water and has isolated
Machine phase.After washing with water, organic layer is evaporated.This crude product is dissolved under reflux 40ml ethyl acetate and 20ml heptan
Until obtaining the solution of a kind of clarification in alkane.This solution is made to be cooled to room temperature.Almost immediately begin to crystallization, and by by its
It is stirred at 23-25 DEG C 21 hours making it crystallize completely.This suspension is cooled to 0-5 DEG C and by its at such a temperature followed by
Continuous stirring 3 hours.After filtration, carry out washing and by it by the cold mixt of product IIa 30ml heptane/ethyl acetate 2:1
It is vacuum dried at 40 DEG C.
Single crystal X-ray measures and confirms that its absolute configuration on 4 Stereocenters is (s, S, S, S).Mp:136-138
DEG C, clarification, colourless
1H-NMR(400MHz,CDCl3):6.04(s,1H),4.22-4.16(m,1H),3.51-3.46(m,1H),2.55-
2.51(m,1H),2.44-2.38(m,1H),2.17-2.09(m,3H),2.07-1.99(m,1H),1.94-1.87(m,1H),
1.80-1.73(m,1H),0.99-0.97(d,3H),0.95-0.93(d,3H),0.91-0.89(d,3H),0.85-0.84(d,
3H)
MS:MH+=254
IR:1775=lactone, 1704=lactams, cm-1(FTIR-transmission microscopy)
2) the alternative method of another kind of the lactams lactone of formula (II) is prepared by direct hydrogenation
[3-isopropyl-5-(4-isopropyl-5-oXo-tetrahydro-furan-2-base) pyrrolidin-2-one] (IIa)
9.0g (19.7mmol) compound Ia and 1.08g palladium/C (5%) joins together with 55ml toluene a hydrogenation burn
In Ping.This hydrogenation is carried out under room temperature and normal pressure.After 24 hours, this conversion it is monitored and makes it tie
Bundle.Carry out filtering and washing to remove catalyst to it with toluene by this reactant mixture filter aid bed.Under vacuo
Evaporating toluene, thus obtain a kind of white crystalline solid, it is compound IIa and the mixture of Evans auxiliary agent.
In order to be separated with auxiliary agent by required compound IIa, this crystalline solid (9.03g) is dissolved in 50ml toluene
In.At room temperature, in the colourless solution of the clarification of gained, 20ml 2N sodium hydroxide solution is added.By the emulsion of gained in room
The lower stirring of temperature 1 hour.Required product is positioned in alkalescence aqueous phase with the form of sodium salt now and toluene phase stayed by described auxiliary agent
In.Aqueous phase 20ml toluene is washed 3 times to be extracted completely by described auxiliary agent.Then, by aqueous phase with 70ml 10% Fructus Citri Limoniae
Acid is acidified, by its pH regulator to 3.In acidization, lactams hydroxy acid II ' a is precipitated out.It is being stirred for 30
After minute, crystal leached and is vacuum dried, thus obtaining the White crystal powder of compound II ' a.
m.p.:152-155℃
1H-NMR(DMSO-d6):0.78(d,3H),0.87-0.91(3xd,9H),1.36(m,1H),1.52(m,1H),
1.72-1.85(cm,3H),1.91-1.98(m,1H),2.19-2.24(m,1H),2.33-2.38(m,1H),3.10-3.18(m,
1H), 3.21-3.25 (m, 1H), 4.73 (broad peak, 1H ,-OH), 7.55 (bs, 1H, NH), 12.03 (broad peak, 1H, CO2H)。
IR:1730,1702,1661,cm-1(FTIR-transmission microscopy)
MS:MH+=272
Then, compound II ' a (3.65g) is redissolved in toluene and is used the p-toluenesulfonic acid list of catalytic amount
Hydrate (0.25g) processes at 50 DEG C.After 5 hours (tlc control), this acid changes into required lactams-lactone
IIa.Toluene 50ml water is extracted twice, then toluene is evaporated in vacuo mutually, obtain fusing point after the drying and be 136-138 DEG C
White crystal compound IIa.Its spectroscopic data and embodiment 1) the spectroscopic data of material identical.
3) preparation of " hydrazoic acid " methyl ester of formula (Va)
At room temperature, 3.0g (10.1mmol) IIIa is dissolved in 15ml dichloromethane.At room temperature, in 25 minutes
It is added thereto to 1.66g (11.1mmol) 3-methyl isophthalic acid-p-tolyl triazenes.After the addition, by this reaction solution at 20-
Stir 2 hours at 25 DEG C.During reaction, nitrogen is produced.In order to carry out post processing, in this solution, add 30ml water.To have
Machine is mutually with 30ml 1N HCl (2x15ml) and 30ml NaHCO38% (2 × 15ml) washs.With 45ml water (3 × 15ml)
Organic facies washed to neutral pH and it is evaporated, thus obtaining the Va of yellow oil form so that it is entering in refrigerator
Row crystallization.
1H-NMR(400MHz,CDCL3):4.40-4.36(m,1H),3.70(s,3H),3.18-3.13(m,1H),2.68-
2.62(m,1H),2.52-2.47(m,1H),2.18-2.10(m,3H),1.98-1.93(q,1H),1.89-1.82(m,1H),
1.74-1.67(m,1H),1.02-1.00(d,3H),0.94-0.91(m,9H)
GC/MS:MH+=312
3b) " hydrazoic acid " methyl ester of formula (Va) is to the hydrogenation of (IIa)
(Va) (4.8mmol) of 1.5g is dissolved in 15ml toluene.It is added thereto to 0.3g Pd/C, (5%) catalyst
It is also hydrogenated by (Engelhard 4522) at room temperature and atmospheric pressure, after 24 hours, completes absorption of hydrogen.Catalyst is leached also
Filter vacuum is evaporated, thus obtains a kind of white powder, itself and compound (IIa)1H-NMR, IR are identical with Tlc.
4) preparation of the lactams-lactone of the Boc-protection of formula (VIa)
By 14g lactams-lactone II a (55.3mmol) together with 6.7mg dimethyl-amino-pyridine (0.055mmol) molten
Solution is in 100ml isopropyl acetate.5.6g (55.3mmol) triethylamine is added in this solution.By this solution at 40-45 DEG C
Heat under internal temperature.At such a temperature, be added thereto in 30 minutes 13.3g (60.8mmol) two carbonic acid two-
Tert-butyl ester solution in 60ml isopropyl acetate.This reaction solution is stirred overnight at 40-45 DEG C.Thereafter, by this reaction
Solution is cooled to room temperature and is diluted it with 160ml heptane.Then, this suspension is cooled to 0-5 DEG C and by it at this
At a temperature of continue stirring 5 hours.After filtration, carry out washing and by it 40 by cold for product cake 50ml heptane/ethyl acetate
It is vacuum dried at DEG C.
1H-NMR(400MHz,CDCl3):4.52-4.48(m,1H,4.34-4.29(m,1H),2.68-2.62(m,1H),
2.55-2.49(m,1H),2.24-2.08(m,4H),2.03-1.94(m,1H),1.81-1.75(m,1H),1.52(s,9H),
1.02-0.98(pst,6H),0.92-0.91(d,3H,0.85-0.84(d,3H)
MS:MH+=354
IR:1777-1760 lactams/lactone/Boc, 1185Boc cm-1(FTIR-transmission microscopy)
Mp:144-145 DEG C, clarification, colourless
5) reaction of compound (VIIIa) is generated by Boc-lactams-lactone (VIa) and aryl-Li compound (VIIa):
In first flask, 8.56g (31.12mmol) aryl bromide (VII ' a) is dissolved in 125mlTHF.This is molten
Liquid cools down under the internal temperature of-70 DEG C.In 1 hour, in this solution, add 19.8ml (31.69mmol) n-fourth
Base lithium 1.6M solution in hexane.Then, this reaction solution becomes pink-red color.This solution is stirred at-70 DEG C 1 little
Time.
In second flask, by that 10.0g Boc-lactams-lactone (VIa) (28.29mmol) is dissolved in 125ml is anhydrous
In THF.This solution is flowed down at argon under the internal temperature of-50 DEG C and cools down.In 30 minutes, at-55 to-50 DEG C
Under, in this solution, add the solution (deriving from first flask) of described aryl-lithium compound (VIIa).
Then, this reactant mixture is stirred 3 hours at-50 DEG C.This reaction is cooled to-70 DEG C and cools down a night.
Second day, by the mode identical with described mode, n-with 1.28g aryl bromide (VII ' a) (4.65mmol) and 3ml
Butyl lithium compounds prepares second part of aryl-lithium compound, and in 10 minutes, is added under the internal temperature of-50 DEG C
In described reactant mixture.This reactant mixture is stirred 4 hours at-50 DEG C.
In order to carry out post processing, in 20 minutes, at 05 DEG C, this reactant mixture is joined 125ml toluene and
On the mixture of 250ml 10% aqueous citric acid solution.This process is exothermicity.By organic facies 150ml citric acid (10% water
Solution) (2 × 75ml) and 150ml NaHCO3[8%], (2 × 75ml) washs.With 150ml water (2 × 75ml) by organic facies
Washing is evaporated to neutral pH and to it, obtains connecing compound (VIIIa) crude product of subalbous amorphous solid.
In order to required compound is purified, this solid of a part (6.72g, 12.22mmol) is dissolved in 60ml second
In alcohol.At 0-5 DEG C, in 20 minutes, in the colourless solution of the clarification of gained, add 28ml 1N lithium hydroxide solution.Make
This mixture is heated up to room temperature (21 DEG C) and it is stirred at such a temperature 1 hour.Thereafter, by part water and ethanol evaporation will
Precipitation 100ml water and the 50ml toluene of gained are diluted, thus obtain a kind of colourless solution.Required product is now currently located in
In alkalescence aqueous phase.This aqueous phase 150ml toluene (3 × 50ml) is washed.75ml ethyl acetate is added in this aqueous phase.To
This reactant mixture adds 7.1g (33.66mmol) citric acid.Now, the product being protonated is positioned in organic facies.First
At room temperature mixture is stirred, then it is stirred at 50 DEG C.After being stirred for 12 hours, to this mixing
Thing adds 3.6g citric acid (17.1mmol) and it is continued at 50 DEG C stirring 24 hours.Then, aqueous phase, Xiang You are isolated
Machine solution adds 7.1g and is positioned at the citric acid in 50ml water.Then, this biphase solution is stirred for 6 hours at 50 DEG C.
Carry out layer separation and be added thereto to 7.1g citric acid the most again.By this reactant mixture the inside temperature of 50 DEG C
It is stirred overnight under degree.In order to carry out post processing, in this reaction solution, at room temperature add 50ml water.Organic facies is used 50ml water
(2 × 25ml) and 50ml NaHCO3[8%], (2 × 25ml) washs.With 50ml water (2 × 25ml), organic facies is washed extremely
It is also evaporated by neutral pH, thus obtains (VIIIa) of the most viscous grease form.
1H-NMR(400MHz,DMSO-d6): (2 kinds of rotamers), 7.52-7.50 (d, 1H), 7.37 (s, 1H),
7.04-7.02(d,1H),6.99(s,1H),4.35-4.31(m,1H),4.06-4.04(t,2H),3.83(s,3H),3.49-
3.46(m,3H),3.25(s,3H),2.51-2.49(m,1H),2.05-1.95(m,4H),1.87-1.80(m,2H),1.63-
1.58(t,1H),1.25(s,9H),0.97-0.95(d,3H),0.92-0.91(d,3H),0.86-0.84(d,3H),0.83-
0.81(d,3H),0.80-0.78(d,3H)。
MS:[MH-Boc]H+=450
Rf=0.45 (heptane: EtOAc=1:1)
5a) compound (VIIIa) is purified by becoming salt to obtain crystallinity Li salt (VIIIa ')
By 30g (55mmol) compound (VIIIa) dissolving crude product in 120ml ethanol, thus obtain the molten of a kind of clarification
Liquid.This solution is cooled to 0 DEG C and in the case of stirring, in 45 minutes, is slowly added to 110mmol LiOH wherein
(2.65g is positioned in 100ml water).This reaction slight exotherm.After 2 hours, HPLC shows that parent material is fully converted into hydroxyl
Acid Li compound (VIIIa ').By distilling about 100ml ethanol-water mixture, the turbid solution of this yellowish is entered
Row part evaporation.The fortified aqueous ethyl acetate (2 × 100ml) of remaining Li-salt is extracted twice.Present by merged
The ethyl acetate 50ml saturated nacl aqueous solution comprising Li salt (XII) carries out returning extraction.Then, organic facies vacuum is steamed
Send out, thus obtain 33.0g foam, be dissolved in 30ml diisopropyl ether.At 0 DEG C, in this solution, add 60ml n-heptane
(isomer mixture).To this mixture inoculation crystal seed and it is placed a night in refrigerator.The crystalline material filter that will be formed
Go out and use the n-heptane that 2 parts (2 × 30ml) is cold that it is washed and by its in vacuum drying oven dried overnight, thus obtain
A kind of crystalline powder of white.
M.p.:62-70 DEG C (melting range)
MS:[M-Li]=566;Li-salt: MH+:574
1H-NMR(600MHz,DMSO-d6): at room temperature, rotamer mixture (about 1:3): 7.58 (d,
min.),7.5(d,maj.),7.43(br.s,min.),7.38(br.s.,maj.),7.05(d,min.), 6.98(d,
maj.),6.1(br.d,-OH,min.+maj.),4.03(br.m.,-OCH2),3.82(s,-OCH3),3.5-3.35(br.m.,-
OCH2,+H2O),3.22(s,-OCH3),3.05(br.m,1H),2.0-1.9(br.m,3H),1.85-1.7(br.m,3H),
1.65-1.55(br.m,1H),1.4-1.3(br.m,4H),1.28(Boc,maj.),0.95(Boc,min.),0.85-0.72
(m, 12H+ heptane).Under 300 ° of Kelvin: 7.52 (br.d, 1H), 7.45 (br.d, 1H), 7.0 (2d, 1H)
IR:3350(br,NH,OH),2960,2932,2873(s,CHnForm), 1686 (C=O), 1581 (-COO-Form),
1515 (amide, aromatics), 1428 (sy.COO-),1267(C-O),1174(C-O-Boc),[cm-1]。
5b)The anti-of compound (VIIIa) is obtained through aryl-alkyl-Mg-class (VIIb) by Boc-lactams-lactone (VIa) Should:
In a dry flask (NO.1,100ml), add the anhydrous THF of 15ml, then it is cooled under argon gas 0
℃.When its temperature reaches 0 DEG C, be added thereto to 6.25ml isopropylmagnesium chloride solution (2.0M, be positioned in THF=
12.5mmol).Then, in 10 minutes, (1.6M is positioned at n-to be added thereto to 7.5ml-butyl lithium solution by syringe
In hexane=12.5mmol).This reactant mixture is stirred 30 minutes at 20-25 DEG C.Thereafter, in 15 minutes, at 25 DEG C
Compound (VII ') is added in this reactant mixture, X=Br, 2.75g (10mmol) solution in the anhydrous THF of 7.5ml, its
Slightly exothermic producing while gas.This Dropping funnel 2mlTHF is washed, then, by this reactant mixture 25
Stir at DEG C at least 3 hours, then, analyze the conversion to VII ' with HPLC and be monitored.In second flask (No.2),
Add 3.53g (10mmol) compound (VIa) and the anhydrous THF of 22.5ml under argon gas.Then, this solution is cooled to-10 DEG C.?
In 1-2 hour, under argon pressure, by polyfluortetraethylene pipe to being positioned in the suspension of (VIa) in No.2 flask addition
Aryl alkyl class (VIIb).Then, this reactant mixture is stirred for 15 hours at-10 DEG C.
After HPLC analyzes and shows that (VIa) converts completely, in 30 minutes, 0 DEG C, in the case of strong agitation this is anti-
Answer and carry out on the mixture of the water that mixture comprises 3.2ml acetic acid at 25ml tBME and 22ml.Then, by aqueous phase separation out
And organic facies 15ml water is extracted three times (45ml altogether).Then, organic facies vacuum evaporation is remaining to obtaining a kind of oily
Thing.This residue is redissolved in 35ml ethanol and it is used at 0 DEG C 0.48g Lithium hydrate solution in 20ml water
Process 5 hours in the case of stirring, thus obtain described lithium salts (VIIIa`).Then, this reactant mixture is concentrated in vacuo
To remove major part ethanol, then with 35ml water and 20ml TBME it it is diluted and is stirred for 5 minutes.Isolate
Aqueous phase is also extracted by machine phase again with 20ml TBME.The organic facies merged comprises unwanted lipotropy aromatic byproducts,
And aqueous phase comprises required lithium salts (VIIIa`).Then, come this by addition 5.3g solid citric acid in the case of stirring
Alkalescence aqueous phase is neutralized, and is then added thereto to 40ml ethyl acetate.By the aqueous phase separation that neutralized out and with another
The citric acid that outer 3.2g is dissolved in 30ml water is replaced.Then, by this reactant mixture at 65 DEG C strong agitation 2 hours from
And complete to lactonize.After HPLC monitoring shows to lactonize completely, in the case of stirring, slowly it is added thereto to 45ml saturated
Sodium bicarbonate solution.Stopping stirring and remove aqueous phase, meanwhile, the organic facies that will comprise described product (VIIIa) uses 25ml water again
Wash twice (50ml altogether).Finally, organic facies is evaporated in vacuo, thus obtains the most viscous a kind of residue (VIIIa), root
Analyzing according to HPLC, it is pure.
5c) by sodium borohydride reduction, by compound (VIIIa ') by Boc-in the case of without (VIIIa)
Amide-lactone (VIa) and the reaction of aryl-Li-class (VIIa) acquisition compound (Xa):
By being heated to 150 DEG C, the three-neck flask of a 750ml is flowed down at argon and is dried.By it at argon
Under be cooled to room temperature after, in this flask add 25g bromide (90.8mmol).Then, by adding the anhydrous (molecule of 440ml
Sieve) oxolane and make this solid dissolve.Then, this solution is cooled to-78 DEG C.At such a temperature, in 30 minutes, Xiang Qi
In be slowly added to the-butyl lithium (1.6M) solution in n-hexane (57ml), thus obtain the colourless solution of a kind of clarification.
This reactant mixture is kept 1 hour at such a temperature.Thereafter, HPLC monitoring indicates halogen-metal completely and exchanges and have
There is the homogenizing coupled product of about 10-15%.
In second flask, will be dissolved 26.73g (75.6mmol) Boc-in the anhydrous THF of 440ml (molecular sieve)
Compound (VIa) is cooled to-70 DEG C.Under argon pressure, in 15 minutes, in this solution, add the Li-class deriving from flask 1
Material (VIIa), thus obtain a kind of almost colourless settled solution.After 20 minutes, HPLC monitoring shows that (VIa) turns completely
Change.By this reactant mixture in the biphasic mixture of 600ml aqueous citric acid solution (10%) and 500ml TBME at 0 DEG C
Strong agitation carries out extinguishing.
Aqueous phase 250ml TBME is extracted.Organic facies (2 × 200ml) aqueous citric acid solution merged is extracted
Take twice, be then extracted twice with (2 × 200ml) sodium bicarbonate (10%) and finally with 2 × 200ml water, it extracted.
By organic facies MgSO4It is dried and is evaporated in vacuo, thus obtain a kind of thick grease.
Then, this grease (48.6g) is dissolved in 500ml ethanol, thus obtains a kind of colourless solution.At 0 DEG C
Under, in the case of stirring, in this solution, add 151ml 1M lithium hydroxide solution (0.151mol).By this reactant mixture
Slowly it is heated up to room temperature after 2 hours, completes lactonic ring open loop (HPLC), thus obtain described lithium salts (VIIIa ').
At 40 DEG C, in 2 hours, in this solution, it is divided into aliquot adds sodium borohydride (3.8g, 100mmol).HPLC
Monitoring shows, after 5h, the 66% of parent material is converted.It is added thereto to 756mg (20mmol) NaBH again4And by its
Continue to be stirred overnight at 40 DEG C.HPLC analyzes and shows to be fully converted into the epimeric mixture of (Xa ').This reaction is mixed
Thing is cooled to 0 DEG C and by being slowly added to 400ml aqueous citric acid solution (～10%) to pH 3 in the case of stirring at 0 DEG C
Destroy the boron hydride of excess.Observe that strong hydrogen overflows.It is concentrated in vacuo to remove ethanol by reactant mixture.By water
Carry out extracting and by the most admixed together with 300ml aqueous citric acid solution again, then by it for this ethyl acetate by ethyl acetate
It is heated up to 50-60 DEG C heat 12 hours, thus lactonizes, and after carrying out being separated and evaporating, with thick oily thing
Form obtains the alcohols (Xa) of 2 kinds of epimerisms, is used TBME/ heptane mixture to crystallize, thus obtains with the ratio of 95:5
A kind of white crystalline solid.Spectroscopic data is consistent with (Xa) epimeric mixture.
6) preparation of the compound (IX) (penultimate precursor) carried out by the direct hydrogenation of compound (VIIIa):
2.75g (5mmol) compound (VIIIa) is dissolved in 30ml ethanol: in the mixture of acetic acid (2:1) and wherein
Add 0.35g catalyst Pd-C (10%), Engelhard 4505.This hydrogenation is to carry out under the pressure of 50 DEG C and 5 bars.?
After 10 hours, sampling shows that it converts the most completely.It is added thereto to some catalyst (0.35g) again and proceeds hydrogenation.?
After 46 hours, almost all of parent material is all converted.This reactant mixture is filtered and with ethanol, it is washed, so
After filter vacuum is evaporated, thus obtain a kind of almost colourless grease.This crude mixture is dissolved in toluene also
With the saturated NaHCO of 25ml3Solution is washed 3 times to neutralize acetic acid and to be extracted in aqueous phase.Toluene is fallen in vacuum evaporation
After, obtain a kind of almost colourless sticky oil thing (2.21g).Tlc (the SiO of this mixture2, heptane: ethyl acetate (1:1)
Show except a small amount of parent material (VIII, Rf0.45) also have outward 4 different speckles, by by Dragendorf ' s reagent spray
It is made to develop the color.It is positioned at the R on topfThe speckle of=0.60 is required compound (IXa).RfIt is two speckles of 0.33 and 0.40
Point is 2 kinds of different epimers of described 01 derivatives (Xa).RfBe 0.55 speckle be compound (XI), it is by Rf
Be 0.33 and 0.40 epimerism compound (Xa) at a higher temperature or hand over ion under acid condition (AcOH)
Change what resin was at room temperature formed.It is observed that similar behavior in HPLC.
By after crude mixture preparative hplc processes described in 2.21g, 20 parts of required compounds can be collected
(IXa),RfThe pure fraction of=0.60, it is by described grease direct crystallization.By this crystalline material heptane recrystallization.
Compound (IXa):
M.p:78-79℃
1H-NMR(400MHz,CDCl3):0.74-0.76(2xd,6H),0.85-0.87(d,3H),0.92-0.94(d,
3H),1.16-1.23(bm,1H),1.38(s,9H,Boc),1.5-1.65(br-m,2H),1.95-2.15(br-m,5H),
2.50-2.35(br-m,1H),2.45-2.52(brm,1H),2.50-2.59(brm,1H),3.28(s,3H),3.50(t,2H),
3.70-3.80(s+m,4H),4.03(t,2H),4.28-4.35(m,2H),6.62(d,1H),6.67(s,1H),6.69(d,
1H)。
IR:3358 (-NH), 1773 (lactones), 1705 (carbamates), 1518 (amide II) cm-1;(FTIR-transmission shows
Micro mirror)
MS:MH+=535.7
Also carry out other " speckle " separating and having carried out qualitative with spectroscopic data to it:
RfThe speckle of=0.55 is equivalent to compound (XIa)
1H-NMR(400MHz,CDCl3):0.77-0.79(d,3H),0.86-0.88(d,3H),0.88-0.90(d,3H),
0.97-0.99 (d, 3H), 1.10-1.30 (broad peak, 9H, boc), 1.78-1.86 (m, 1H), 2.0-2.06 (m, 2H), 2.08-
2.16(brm,3H),2.50-2.60(brm,1H),3.27(s,3H),3.50(t,2H),3.77(s,3H),4.0-4.10(brm,
3H), 4.20-4.40 (broad peak, 2H), 6.72-6.74 (d, 1H), 6.75-6.77 (d, 1H), 6.83 (s, 1H).
m.p.:63-69℃
IR:3057,2970,1773 (lactone), 1688 (Boc), 1515,1390,1368 [cm-1]
MS:MH+=534;M-NH4 +=551
RfThe speckle of=0.40 is equivalent to compound (Xa)-epimer 1, and (it is poor that X-ray structural analysis is shown to be syn-
To isomer:
1H-NMR(400MHz,CDCl3):0.82-0.88(3xd,9H),0.92-0.94(d,3H),1.40(s,9H),
1.80-1.93(brm,2H),2.03-2.11(brm,4H),2.37-2.45(brm,1H),3.32(s,3H),3.35(t,2H),
3.83(s,3H),4.05-4.20(brm,3H),4.25(d,1H),4.60(d,1H),6.80(d,1H),4.83(dd,1H),
6.95(s,1H)。
MS:M+NH4 +=569;M-H=550
7) preparation of the compound (IXa) carried out by compound (VIIIa) being carried out direct hydrogenation in EtOH:
H
2
O (9:1) at atmospheric pressure and room temperature, use Pd-C, 10%, wet, JM-type 39:
5.5g (10mmol) compound (VIIIa) is dissolved in the mixture of 90ml ethanol and 10ml water.To this mixing
Thing adds 5g catalyst Pd-C (10%), water content about 50%, derives from Matthey, 39 types.By this mixture in room temperature and just
Stir 20 hours under normal pressure.Now, being converted into 98% and define the required compound of 66% of compound (VIIIa)
(IXa), the alcohols (Xa) of the epimerism of 28% and the pyrrolidine lactone (XIa) of 4%.It is further continued for hydrogen at identical conditions
Change 48 hours, not it is possible to additionally incorporate catalyst.Thereafter, catalyst leached and under reduced pressure evaporates solvent, thus obtaining one
Grease (5.9g), according to HPLC, it comprises the compound (IXa) of 89% and comprises the compound (XIa) of 5% and 5% initial
Material (VIIIa).This grease is processed and it is entered at 0 DEG C together with 10ml n-heptane (isomer mixture)
It is also inoculated with minority specioz (IXa) by row stirring when product starts to crystallize.This flask is stored in refrigerator one
It is also deposited 24 hours at-18 DEG C by night again.Product is leached and washs by the coldest n-heptane of a small amount of volume,
Thus after vacuum drying, obtain required product, HPLC, TLC and1H-NMR shows that it is pure.
8) by by compound (VIIIa) in EtOAc at 6 bars, use catalyst Pd-C at 20-60 DEG C, 10%, exist
Carry out in the case of potassium formate hydrogenating the compound (Xa) carried out, the preparation of (alcohols of syn-anti epimerism)
The compound (VIIIa) of 22.0g (40mmol) grease form is dissolved in 150ml ethyl acetate.
It is added thereto to 10g Pd/C (10%), Engelhard 4505 type and 500mg potassium formate with the acid to this catalyst
Property component buffers.Hydrogenate under 6 bars and room temperature during beginning, thereafter its temperature is risen to 60 DEG C and hydrogenate.At 8 days
After, then it is added thereto to catalyst (5g), after nine days, its conversion ratio is 91% and only with the ratio shape of 93:7 (syn:anti)
Become the alcohol of 2 kinds of epimerisms, compound (IXa) will not be decomposed into further or form compound (XIa).Catalyst is leached also
Solvent is fallen in vacuum evaporation, thus obtains a kind of grease, crystallizes (19.0g) when it at room temperature stands.By this material tert-
Butyl methyl ether (20ml) and n-heptane (60ml, isomer mixture) recrystallization it is connect with crystal seed at 20 DEG C
Kind.After crystallization is almost complete (2 hours), at 20 DEG C, then it is added thereto to 40ml n-heptane, is stirred for 2 hours, will
It stores a night in refrigerator, filters, washs it by cold n-heptane, acquisition white crystalline material is dried (syn/
Anti ratio=93:7, HPLC).
M.p.:69-71 DEG C of syn/anti alcohol mixture.
8) preparation of compound (Xa ') (deriving from the hydroxy-acid salt of the alcohol (Xa) of syn-anti epimerism)
The epimeric mixture (ratio about 9:1) of 1g (1.8mmol) crystalloid alcohol (Xa) is dissolved in 10ml ethanol
In.This solution is cooled to 0 DEG C and is added thereto to Lithium hydrate (3.6mmol) in water (4ml) in the case of stirring
Solution.By it after stirring for 2 h at ambient temperature, its reaction is completely.It is removed by distillation major part ethanol and by remnants
Aqueous phase extract by 2 × 20ml ethyl acetate.The acetic acid ethyl ester extract 5ml saline merged is washed, so
After evaporated, it is thus achieved that a kind of oily solid.It is added thereto to 5ml n-heptane so that this substance crystallization.By this crystallization suspension
In refrigerator, store a night, then it is filtered, by cold n-heptane it washed and be vacuum dried, thus obtaining
A kind of white solid.
M.p.:118 128 DEG C (melting range)
MS:[M-Li]-=568;MH+=576
IR:FTIR transmission microscopy: 3440,3355,3167 (br, NH, OH);2958,2874(aliph.-CH),1686
(C=O, Boc), 1605 (as, COO-), 1555 (amide-II), 1514,1438 (sy, COO-),1367,1258,1171,1028,
[cm-1]
The compound that 9) carried out by (IXa) (IXa '), the preparation of the Li-salt of hydroxy acid
1g (1.86mmol) crystalloid compound (IXa) is dissolved in 10ml ethanol.88.6mg is added in this solution
(3.7mmol) Lithium hydrate solution in 5 ml of water.This uniform reactant mixture is stirred at room temperature 2 hours.Now,
HPLC shows that it converts completely.By the evaporation of this solution for vacuum to remove major part ethanol.Aqueous phase 2 × 20ml ethyl acetate is entered
Row extraction.The ethyl acetate 5ml saline merged is washed, then it is evaporated, thus obtain one and have
The solid of viscosity.At 0 DEG C, in the case of stirring, it is added thereto to 10ml n-heptane so that this substance crystallization.By this crystallization
Suspension stores a night in refrigerator, then filters it and washs it by cold n-heptane, its vacuum is done
Dry, thus obtain a kind of white solid.
M.p.:88 98 DEG C (melting range)
IR:FTIR-transmission microscopy: 3573 (-OH), 3377 (-NH), 2955,2933,2871,1679 (Boc), 1572
(COO-), 1514 (amide-II), 1439,1423 (COO-),1366,1260,1239,1170,1122,1026[cm-1]
MS:[M-Li]-=552;MH+=560
10) with Pd-C, compound (VIIIa ') (deriving from the hydroxy-acid salt of (VIIIa)) is hydrogenated to epimeric mixture
The compound of form (Xa ')
2.8g (5.0mmol) carboxyl-Li-salt (compound VIIIa ') is dissolved in 40ml isopropanol.It is added thereto to
2.5g Pd-C (10%), JM type 39, wet, and it is hydrogenated at 25 DEG C under 0.2 bar a night (17 hours).At this moment, chemical combination
Thing (VIIIa ') be converted into 86% (HPLC).Its temperature is risen to 50 DEG C and is further continued for hydrogenating 24 hours.At 41 hours
After, only observed minor variations at conversion aspect, but the ratio of syn/anti epimerism alcohol is from 83% syn/17%
Anti becomes 67% syn/33% anti.Then be added thereto to some catalyst (1g) and it is hydrogenated at 50 DEG C 6 again therefore,
Hour.At this moment, HPLC analyzes and shows to convert the most further, but syn/anti ratio becomes again 62:38.It is being added without catalysis
In the case of agent, it is hydrogenated 36 hours at 50 DEG C again.At this moment, HPLC analyzes and shows that syn/anti ratio is 45:55, but
The conversion of parent material no longer changes (83%).It shows under the cited reaction conditions, the alcohol of syn epimerism and anti
Change is there is in epimer by oxidation-reduction circulation.Stop hydrogenation, catalyst is leached and solvent is evaporated, it is thus achieved that one
Plant semi-solid grease.
11) Li-salt (VIIIa ') is reduced into through (Xa ') by carrying out reducing in alcohol-water (1:1) with sodium borohydride
(Xa):
2.3g (4mmol) Li-salt (VIIIa ') is at room temperature dissolved in the mixture of 10ml water and 10ml ethanol.Will
This solution is heated up to 40 DEG C and in 1 hour, is divided into aliquot wherein and adds sodium borohydride (151mg, 4mmol).HPLC monitors
Showing after 4 hours, the 66% of parent material is converted.It is added thereto to 38mg (1mmol) NaBH again4And by it at 40 DEG C
Continue to be stirred overnight.HPLC analyzes and shows to convert completely.By making its pH to 3 in the upper extinguishing of 40ml aqueous citric acid solution (10%)
Destroy the boron hydride of excess.It is concentrated in vacuo to remove ethanol by this reactant mixture.Aqueous phase ethyl acetate is extracted
Take and ethyl acetate mixed with 10ml aqueous citric acid solution mutually again, be then heated up to 50-60 DEG C heat 2 hours from
And lactonize, after carrying out being separated and evaporating, obtain the alcohols (Xa) of 2 kinds of epimerisms with sticky oil thing likeness in form,
Used TBME/ heptane recrystallization, obtained a kind of white solid with the ratio of 95:5.HPLC and spectroscopic data and (Xa) mixture
Other sample consistent.
Other solvent mixture such as THF/ water or iso-propanol/water or only use water or there is the ethanol of 20 volume % water also
It it is the good solvent of this borohydride reduction.
12) the Barton-McCombie-approach of compound (IXa) is obtained
A) compound (XVa)=imidazoles-1-bamic acid O-{ (S)-2-[(S)-2-t-butoxy carbonylamino-2-
((2S, 4S)-4-isopropyl-5-oXo-tetrahydro-furan-2-base)-ethyl]-1-[4-methoxyl group-3-(3-methoxyl group the-the third oxygen
Base)-phenyl]-3-methyl-butvl } preparation of ester
The compound (Xa) (1.66g, 3mmol) of epimerism is dissolved in toluene (18mL) and is added thereto to 1,1-
Thiocarbonyl group-diimidazole (0.804g, 4.5mmol), is then added thereto to dimethylaminopyridine (0.037g).By this reaction
Mixture is stirred at room temperature a night.In order to carry out post processing, it is added thereto to NaHCO3Saturated aqueous solution (20mL) is also carried out
Layer separates.Organic layer is used saturated NaHCO3Aqueous solution (20mL) and water (20mL) extract.By organic layer at anhydrous MgSO4
On be dried and be evaporated off under reduced pressure solvent, thus obtain the crude product of 2.08g viscous liquid form.By quick for this crude product silica gel
Column chromatography is purified, and with tert-butyl-methyl ether as flowing phase, thus the compound (XVa) obtaining white foam form is pure
Product.The structure that 1H-NMR, IR and HR-MS spectra of this product is proposed is diastereomer (epimer)
Mixture.It is made owing to there is rotamer1H-NMR spectrum complicates.1H-NMR(400MHz,354K,d6-DMSO):
0.65-0.99(m,12H),1.42(s,9H),1.44-2.44(m,10H),3.24(s,3H),3.47(t,2H),3.75(s,
3H),3.76-3.90(m,1H),4.01(t,2H),4.06-4.40(m,1H),4.73-4.89(m,1H),6.81-7.03(m,
3H), 7.05 (wide s, 1H), 7.62 (wide s, 1H), 8.28 (wide s, 1H).FT-IR (transmission): 3317,3125,2961,2933,
2875,2836,1769,1701,1604,1591,1517,1469,1427,1390,1366,1331,1290,1265,1221,
1168,1143,1120,1097,1064,1046,1026,968,949,886,811,753,725,694,666,646cm-1。
HR-MS:C34H51N3O8The MNa of S+Value of calculation=684.32891, measured value: 684.32894;MK+Value of calculation=
700.30284, measured value: 700.30306.
B) by with tributyltin hydride compound (XVa) being prepared the most originally compound (IXa):
By compound (XVa) (=imidazoles-1-bamic acid O-{ (S)-2-[(S)-2-t-butoxy carbonylamino-2-
((2S, 4S)-4-isopropyl-5-oXo-tetrahydro-furan-2-base)-ethyl]-1-[4-methoxyl group-3-(3-methoxyl group the-the third oxygen
Base)-phenyl]-3-methyl-butvl } ester) (0.4g, 0.604mmol) be dissolved in toluene (8mL).This solution is heated to 100
℃.At such a temperature, it is added thereto to tributyltin hydride (0.916g) by syringe, is subsequently adding AIBN (0.01984g)
Solution in oxolane (0.4mL).This reactant mixture is stirred 1 hour at 100 DEG C, thereafter, then is added thereto to
Another part is positioned at the AIBN (0.01984g) in oxolane (0.4mL).It is further continued for it at 100 DEG C stirring 1 hour and leading to
Cross and this reactant mixture is joined this reaction extinguishing in the cold methanol (10mL) of-20 DEG C.It is added thereto to toluene
(10mL) and by this mixture 1N HCl/water solution (2x10mL) and water (10mL) extract.Water layer is merged and uses toluene
(10mL) it is extracted.Organic layer is merged, uses anhydrous Na2SO4It is dried and under reduced pressure evaporates solvent.By this oily
Product crude product silica gel flash column chromatography is purified, and carries out eluting by hexane/isopropyl alcohol (9:1), obtains compound (IXa).
According to HPLC and 1H-NMR, this product is identical with reference to sample with compound IXa's.
C) by with three (trimethyl silyl) silane compound (XVa) being prepared the most originally compound (IXa):
By compound (XVa) (=imidazoles-1-bamic acid O-{ (S)-2-[(S)-2-t-butoxy carbonylamino-2-
((2S, 4S)-4-isopropyl-5-oXo-tetrahydro-furan-2-base)-ethyl]-1-[4-methoxyl group-3-(3-methoxyl group the-the third oxygen
Base)-phenyl]-3-methyl-butvl } ester) (0.4g, 0.604mmol) be dissolved in toluene (4mL) and tert-lauryl mercaptan
(4mL) in mixture.This solution is heated to 100 DEG C.Be added thereto to three (trimethyl silyl) silane (774.5mg,
3mmol), the AIBN (20mg) solution in toluene (0.4mL) then it is added thereto to.By this reactant mixture at 100 DEG C
Stir 15 minutes and be poured upon on the cold methanol (10mL) of-20 DEG C with by this reaction extinguishing.It is added thereto to toluene
(10mL) and by this mixture 1N HCl/water solution (2x10mL) and water (10mL) extract.Water layer is merged and uses toluene
(10mL) it is extracted.Organic layer is merged, is dried with anhydrous sodium sulfate, evaporates solvent.By this crude product silicon
Glue flash column chromatography is purified, thus obtains the sterling (30mg, yield is 18.5%) of compound 4.According to HPLC and 1H-
NMR, this product is identical with reference to sample with compound IXa's.
13) by as auxiliary agent (+) conjunction of two-pseudoephedrine precursor (Ia ' vi) that carries out of-(1S, 2S)-puppet-ephedrine
Become: Lit.:A.Myers et al., J.A.C.S., 119,6496 (1997)
Flow down at argon be dried by being heated to 150 DEG C of three-neck flasks to a 100ml.By it at argon
Under be cooled to room temperature after, be added thereto to the dry lithium chloride of 2.54g (60mmol).Then, in the case of stirring wherein
Add 3.15ml and be dissolved in the diisopropylamine in the anhydrous THF of 12ml.The suspension of gained is cooled to-78 under argon gas
℃.In the case of stirring, at-78 DEG C, in this suspension, add 13ml 1.6M butyl lithium in hexane by syringe
Solution, thus obtain LDA.After by this suspension stirred for another 15 minutes, at-78 DEG C, it is added thereto to by syringe
The N-isovaleryl that 2.5g is dissolved in 10ml THF-(S, S)-puppet-ephedrine (10mmol).Then, this suspension is existed
0 DEG C it is heated up in 30 minutes.At such a temperature, being added thereto to 1.18g (5.5mmol) anti-form-1 by syringe, 4-bis-is bromo-
2-butylene solution in 5ml THF.It is further continued for it at 0-5 DEG C stirring 30 minutes.After agitation, by this reactant mixture
It is stirred at room temperature a night.HPLC monitoring shows that it converts completely.By this reactant mixture at 80ml aqueous ammonium chloride solution and
Extinguishing on 50ml TBME.Aqueous phase 25ml TBME is extracted twice.Then, the organic facies saline (50ml) that will be merged
Washing, uses MgSO4It is dried, finally it is filtered and be evaporated in vacuo, thus obtain the most viscous a kind of grease,
After it being evacuated under a high vacuum, obtain a kind of white foam.MS, at d6In-DMSO, in room temperature (300 ° of K) and the temperature of rising
Under degree (394 ° of K)1H-NMR confirms its structure.2 kinds of rotamers that this compound is (～2:1) with ratio under RT
Presented in mixture.
MS:551(MH+)
IR:3350 (br, OH), 2960,1608 (amide), 1450,1407,1030,970,755,700 [cm-1]。
1H-NMR,600MHz(d6-DMSO): complicated spectrum, 2 set the signals, (mixture of rotamer under 300 ° of K
(～2:1).
Claims (9)
1. prepare wherein R for one kind3And R4It is C independently of one another1-C7Alkyl and Act are selected from tertbutyloxycarbonyl or benzene methoxycarbonyl group
Activated group, R1It is C1-6Alkoxy-C1-6Alkyl oxy；R2It is C1-4The side of the compound or its salt of the formula (VIII) of alkoxyl
Method；
It includes with wherein Y selected from-Li ,-MgX, and wherein X is halogen, is optionally chosen from Cl, I or Br；And R1It is C1-6Alkoxy-C1-6
Alkyl oxy, R2It is C1-4The compound of the formula (VII) of alkoxyl
Open lactams lactone or the step of lactam nucleus of its salt of the N-activation of formula (VI):
Wherein
R3It is C1-7Alkyl；
R4It is C1-7Alkyl；And
Act is selected from tertbutyloxycarbonyl or the activated group of benzene methoxycarbonyl group.
2. the method for claim 1, the lactams the lactone wherein N-of described formula (VI) activated and the change of following formula
Compound reacts:
3. the compound or its salt of formula (VIII)
Wherein
R3It is C1-7Alkyl；
R4It is C1-7Alkyl；
R1It is C1-6Alkoxy-C1-6Alkyl oxy；
R2It is C1-4Alkoxyl；And
Act is selected from tertbutyloxycarbonyl or the activated group of benzene methoxycarbonyl group.
4. compound as claimed in claim 3, it has following formula
5. the compound as described in claim 3 or 4, it has following formula
6. prepare wherein R for one kind3And R4It is C independently of one another1-C7Alkyl, R1It is C1-6Alkoxy-C1-6Alkyl oxy, R2It is C1-4
Alkoxyl and Act are the methods of formula (IX) compound or its salt selected from tertbutyloxycarbonyl or the activated group of benzene methoxycarbonyl group,
A () includes the benzylic carbonyl of formula as defined in claim 3 to 4 (VIII) compound is reduced into methylene moiety；
Or
B () includes preparing wherein R3And R4It is C independently of one another1-C7Alkyl, R1It is C1-6Alkoxy-C1-6Alkyl oxy, R2It is
C1-4Alkoxyl and Act are the sides of the compound or its salt of the formula (X) selected from tertbutyloxycarbonyl or the activated group of benzene methoxycarbonyl group
Method
Described method includes the benzylic carbonyl of formula defined in claim 4 to 5 (VIII) compound is reduced into hydroxylic moiety；
Then it is formula (IX) compound by formula (X) hydrogenation of compounds.
7. prepare wherein R for one kind3And R4It is C independently of one another1-C7Alkyl, R1It is C1-6Alkoxy-C1-6Alkyl oxy, R2It is C1-4
Alkoxyl and Act are the sides of the compound or its salt of the formula (XII) selected from tertbutyloxycarbonyl or the activated group of benzene methoxycarbonyl group
Method,
It includes preparing formula (IX) compound in accordance with the method for claim 6；
Then amine or its salt of the compound of Formula IX with Formula X III are reacted
8. prepare wherein R for one kind3And R4It is C independently of one another1-C7Alkyl, R1It is C1-6Alkoxy-C1-6Alkyl oxy, R2It is C1-4
The method of the compound or its salt of the formula (XIV) of alkoxyl,
It includes below step:
-the compound or its salt manufacturing Formula VIII as claimed in claim 1, and
-the compound or its salt manufacturing Formula IX as claimed in claim 6.
9. method as claimed in claim 8, it is characterised in that described formula (XIV) compound is aliskiren.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0521083.6A GB0521083D0 (en) | 2005-10-17 | 2005-10-17 | Organic compounds |
| GB0521083.6 | 2005-10-17 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006800035979A Division CN101111493B (en) | 2005-10-17 | 2006-10-16 | 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103121995A CN103121995A (en) | 2013-05-29 |
| CN103121995B true CN103121995B (en) | 2016-08-03 |
Family
ID=35451886
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210566662.6A Active CN103121995B (en) | 2005-10-17 | 2006-10-16 | 3-alkyl-5-(4-alkyl-5-oXo-tetrahydro furan-2-base) pyrrolidin-2-one derivatives as the intermediate of synthesis renin inhibitor |
| CN2006800035979A Active CN101111493B (en) | 2005-10-17 | 2006-10-16 | 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006800035979A Active CN101111493B (en) | 2005-10-17 | 2006-10-16 | 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors |
Country Status (30)
| Country | Link |
|---|---|
| US (2) | US7772405B2 (en) |
| EP (1) | EP1948643B1 (en) |
| JP (3) | JP5356031B2 (en) |
| KR (1) | KR101294432B1 (en) |
| CN (2) | CN103121995B (en) |
| AR (1) | AR058089A1 (en) |
| AU (1) | AU2006303489B2 (en) |
| BR (1) | BRPI0617492A2 (en) |
| CA (2) | CA2625034C (en) |
| CY (1) | CY1114308T1 (en) |
| DK (1) | DK1948643T3 (en) |
| EC (1) | ECSP088368A (en) |
| ES (1) | ES2427098T3 (en) |
| GB (1) | GB0521083D0 (en) |
| HK (1) | HK1120509A1 (en) |
| HR (1) | HRP20130793T1 (en) |
| IL (1) | IL190330A (en) |
| JO (1) | JO2926B1 (en) |
| MY (1) | MY145466A (en) |
| NO (1) | NO342854B1 (en) |
| NZ (1) | NZ567042A (en) |
| PE (2) | PE20120581A1 (en) |
| PL (1) | PL1948643T3 (en) |
| PT (1) | PT1948643E (en) |
| RU (1) | RU2432354C2 (en) |
| SI (1) | SI1948643T1 (en) |
| TN (1) | TNSN08170A1 (en) |
| TW (1) | TWI395733B (en) |
| WO (1) | WO2007045420A2 (en) |
| ZA (1) | ZA200802632B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0521083D0 (en) * | 2005-10-17 | 2005-11-23 | Novartis Ag | Organic compounds |
| DE102005052195A1 (en) | 2005-10-28 | 2007-05-03 | Reuter Chemischer Apparatebau Kg | Process for the preparation of chiral octenoic acid derivatives |
| BRPI0809678A2 (en) * | 2007-04-03 | 2014-10-07 | Novartis Ag | METHODS |
| AU2008265181A1 (en) * | 2007-06-19 | 2008-12-24 | Novartis Ag | Process for the synthesis of intermediates of renin inhibitors such as aliskiren |
| DE102007049039A1 (en) * | 2007-10-11 | 2009-04-16 | Reuter Chemischer Apparatebau Kg | Process for the preparation of 8-hydrazino-8-aryl-octanoyl derivatives and their use |
| EP2189442B1 (en) * | 2008-11-20 | 2014-10-01 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process and intermediates for the preparation of aliskiren |
| KR101755052B1 (en) * | 2009-08-11 | 2017-07-06 | 노파르티스 아게 | The ring opening of lactones and lactams |
| US8203005B2 (en) * | 2009-10-29 | 2012-06-19 | Carbo Design Llc | Manufacturing process for enantiomerically pure 8-aryloctanoic acids as Aliskiren |
| US20110137047A1 (en) * | 2009-12-07 | 2011-06-09 | CarboDesign LLC | Process for enantiomerically pure 8-Aryloctanoic acids as Aliskiren |
| CN101774986B (en) * | 2010-01-06 | 2012-03-28 | 浙江天宇药业股份有限公司 | Method for preparing aliskiren and intermediate thereof |
| CN102241650B (en) * | 2010-05-14 | 2014-05-07 | 浙江九洲药业股份有限公司 | Intermediate compound for preparing aliskiren and related preparation method |
| CN102485722B (en) * | 2010-12-06 | 2014-05-07 | 博瑞生物医药技术(苏州)有限公司 | Aliskiren, its intermediates and medicinal salt, as well as preparation method thereof |
| CN102775393B (en) * | 2011-05-09 | 2014-08-27 | 上海现代制药股份有限公司 | Preparation method for intermediate of medicine |
| US8703976B2 (en) | 2011-10-02 | 2014-04-22 | Milan Soukup | Manufacturing process for 8-aryloctanoic acids such as Aliskiren |
| CN102746182B (en) * | 2012-07-27 | 2014-09-03 | 浙江普洛医药科技有限公司 | Preparation method of Aliskiren |
| CN103059012B (en) * | 2013-01-30 | 2016-06-22 | 浙江海翔药业股份有限公司 | 1,8-dicarbapentaborane-4,5-epoxide and preparation method thereof |
| CN106220528B (en) * | 2014-02-28 | 2018-05-08 | 华润双鹤药业股份有限公司 | 4- positions epimer, the preparation method and the usage of aliskiren |
| CN105294612A (en) * | 2014-06-05 | 2016-02-03 | 山东威智医药工业有限公司 | Aliskiren intermediate, and preparation method therefor and application thereof |
| US10087190B1 (en) * | 2017-04-24 | 2018-10-02 | Purdue Research Foundation | Lactones |
| CN114315749B (en) * | 2021-12-13 | 2024-04-26 | 湖南华腾医药有限公司 | Method for synthesizing aliskiren intermediate by continuous flow microreactor |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1117960A (en) * | 1994-04-18 | 1996-03-06 | 西巴-盖尔基股份公司 | Novel delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides |
| CN1551868A (en) * | 2001-09-07 | 2004-12-01 | �����ɷ� | Method for the production of 2-pyrrolidone |
| WO2005051895A1 (en) * | 2003-11-26 | 2005-06-09 | Novartis Ag | Organic compounds |
| WO2005090305A1 (en) * | 2004-03-19 | 2005-09-29 | Speedel Experimenta Ag | 5-amino-4-hydroxy-7-(1h-indolmethyl)-8-methylnonamide derivatives as renin inhibitors for the treatment of hypertension |
| CN101111493B (en) * | 2005-10-17 | 2013-02-13 | 诺瓦提斯公司 | 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5659065A (en) | 1994-04-18 | 1997-08-19 | Novartis Corporation | Alpha-aminoalkanoic acids and reduction products |
| US5606078A (en) | 1994-04-18 | 1997-02-25 | Ciba-Geigy Corporation | 3,5-Disubstituted tetrahydrofuran-2-ones |
| EP1200390B1 (en) | 1999-07-29 | 2008-08-27 | Speedel Pharma AG | Production of n-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides |
| FR2801051B1 (en) * | 1999-11-17 | 2001-12-14 | Adir | NOVEL AMINOPYRROLINE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| US6310904B1 (en) | 2000-05-31 | 2001-10-30 | Honeywell International, Inc. | Measurement method to facilitate production of self-aligning laser gyroscope block |
| PT1215201E (en) | 2000-12-14 | 2007-02-28 | Speedel Pharma Ag | Process for the preparation of aryloctanoyl amides |
| GB0212410D0 (en) * | 2002-05-29 | 2002-07-10 | Novartis Ag | Organic compounds |
| BRPI0417543A (en) * | 2003-12-12 | 2007-03-27 | Wyeth Corp | quinolines useful in treating cardiovascular disease |
| EP1582523A1 (en) * | 2004-04-02 | 2005-10-05 | Ludwig-Maximilians-Universität München | Method of preparing organomagnesium compounds |
| GB0419361D0 (en) | 2004-08-31 | 2004-10-06 | Novartis Ag | Organic compounds |
| GB0511686D0 (en) * | 2005-06-08 | 2005-07-13 | Novartis Ag | Organic compounds |
-
2005
- 2005-10-17 GB GBGB0521083.6A patent/GB0521083D0/en not_active Ceased
-
2006
- 2006-10-13 AR ARP060104497A patent/AR058089A1/en not_active Application Discontinuation
- 2006-10-15 JO JO2006369A patent/JO2926B1/en active
- 2006-10-16 NZ NZ567042A patent/NZ567042A/en not_active IP Right Cessation
- 2006-10-16 CN CN201210566662.6A patent/CN103121995B/en active Active
- 2006-10-16 SI SI200631641T patent/SI1948643T1/en unknown
- 2006-10-16 EP EP06828821.6A patent/EP1948643B1/en active Active
- 2006-10-16 TW TW095138055A patent/TWI395733B/en not_active IP Right Cessation
- 2006-10-16 KR KR1020087009098A patent/KR101294432B1/en active IP Right Grant
- 2006-10-16 PE PE2011001455A patent/PE20120581A1/en active IP Right Grant
- 2006-10-16 RU RU2008119276/04A patent/RU2432354C2/en not_active IP Right Cessation
- 2006-10-16 PL PL06828821T patent/PL1948643T3/en unknown
- 2006-10-16 BR BRPI0617492-2A patent/BRPI0617492A2/en not_active Application Discontinuation
- 2006-10-16 CN CN2006800035979A patent/CN101111493B/en active Active
- 2006-10-16 PT PT68288216T patent/PT1948643E/en unknown
- 2006-10-16 JP JP2008535948A patent/JP5356031B2/en active Active
- 2006-10-16 US US12/088,457 patent/US7772405B2/en active Active
- 2006-10-16 WO PCT/EP2006/009970 patent/WO2007045420A2/en active Application Filing
- 2006-10-16 CA CA2625034A patent/CA2625034C/en not_active Expired - Fee Related
- 2006-10-16 AU AU2006303489A patent/AU2006303489B2/en not_active Ceased
- 2006-10-16 PE PE2006001252A patent/PE20070792A1/en active IP Right Grant
- 2006-10-16 CA CA2829487A patent/CA2829487A1/en not_active Abandoned
- 2006-10-16 DK DK06828821.6T patent/DK1948643T3/en active
- 2006-10-16 ES ES06828821T patent/ES2427098T3/en active Active
-
2008
- 2008-03-20 IL IL190330A patent/IL190330A/en active IP Right Grant
- 2008-03-25 ZA ZA200802632A patent/ZA200802632B/en unknown
- 2008-04-15 MY MYPI20081108A patent/MY145466A/en unknown
- 2008-04-15 EC EC2008008368A patent/ECSP088368A/en unknown
- 2008-04-16 TN TNP2008000170A patent/TNSN08170A1/en unknown
- 2008-05-16 NO NO20082263A patent/NO342854B1/en not_active IP Right Cessation
- 2008-12-19 HK HK08113800.5A patent/HK1120509A1/en not_active IP Right Cessation
-
2010
- 2010-06-25 US US12/823,699 patent/US8198465B2/en active Active
-
2012
- 2012-09-26 JP JP2012213001A patent/JP5792139B2/en active Active
-
2013
- 2013-08-22 HR HRP20130793TT patent/HRP20130793T1/en unknown
- 2013-09-02 CY CY20131100754T patent/CY1114308T1/en unknown
-
2014
- 2014-05-21 JP JP2014105430A patent/JP2014196312A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1117960A (en) * | 1994-04-18 | 1996-03-06 | 西巴-盖尔基股份公司 | Novel delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides |
| CN1551868A (en) * | 2001-09-07 | 2004-12-01 | �����ɷ� | Method for the production of 2-pyrrolidone |
| WO2005051895A1 (en) * | 2003-11-26 | 2005-06-09 | Novartis Ag | Organic compounds |
| WO2005090305A1 (en) * | 2004-03-19 | 2005-09-29 | Speedel Experimenta Ag | 5-amino-4-hydroxy-7-(1h-indolmethyl)-8-methylnonamide derivatives as renin inhibitors for the treatment of hypertension |
| CN101111493B (en) * | 2005-10-17 | 2013-02-13 | 诺瓦提斯公司 | 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| Practical synthesis of an orally active renin inhibitor aliskiren;Hua Dong，等;《Tetrahedron Letters》;20050728;第46卷(第37期);第6337-6340页 * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103121995B (en) | 3-alkyl-5-(4-alkyl-5-oXo-tetrahydro furan-2-base) pyrrolidin-2-one derivatives as the intermediate of synthesis renin inhibitor | |
| SG185318A1 (en) | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid | |
| NO336663B1 (en) | Process for dissolving an enantiomeric mixture of 1-amino-2-vinylcyclopropyl carboxylic acid derivatives | |
| US7767831B2 (en) | Process for preparing renin inhibitors | |
| CN101679213A (en) | New methods | |
| HUE032484T2 (en) | Production method of intermediate compound for synthesizing medicament | |
| CN107428776A (en) | Manufacture the 4,5,6,7 tetrahydrochysene isoxazoles simultaneously alcohol of [5,4 c] pyridine 3 | |
| CN113717176A (en) | Method for preparing remazolam | |
| Soengas et al. | Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo [2.2. 1] heptanes. Part 2: Synthesis of (1S, 2R, 3S, 4S, 5R)-3, 4, 5-trihydroxy-2-aminocyclopentanecarboxylic acid | |
| KR20080048042A (en) | Synthesis of renin inhibitors involving a cycloaddition reaction | |
| Breuning et al. | Enantioselective total synthesis of the tricyclic 9-oxabispidine (1R, 2S, 9S)-11-methyl-13-oxa-7, 11-diazatricyclo [7.3. 1.02, 7] tridecane | |
| ITMI991950A1 (en) | PROCEDURE FOR THE SYNTHESIS OF RITOMAVIR | |
| Bowman et al. | Cyclisation of α-chiral aminyl radicals | |
| EP1817273A2 (en) | Method for preparing diastereoisomers of 4-hydroxy isoleucine | |
| KR0150566B1 (en) | A process for preparing stereo active 3-amino heterocyclic compound | |
| CN102030734A (en) | Method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof | |
| CN107021911A (en) | A kind of method for preparing levo-oxiracetam crystal formation II |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: Basel Applicant after: Novartis Ag Address before: Basel Applicant before: Novartis AG |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: NOVARTIS AG TO: NOVARTIS CO., LTD. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170504 Address after: Dublin, Ireland Patentee after: Norton pharmaceuticals Address before: Basel Patentee before: Novartis Ag |
|
| TR01 | Transfer of patent right |